U.S. patent application number 17/708660 was filed with the patent office on 2022-07-21 for methods for treating il-6 mediated inflammation without immunosuppression.
The applicant listed for this patent is Novo Nordisk A/S. Invention is credited to Michael H. Davidson, Madhav N. Devalaraja, Rahul Kakkar.
Application Number | 20220227856 17/708660 |
Document ID | / |
Family ID | 1000006242520 |
Filed Date | 2022-07-21 |
United States Patent
Application |
20220227856 |
Kind Code |
A1 |
Devalaraja; Madhav N. ; et
al. |
July 21, 2022 |
METHODS FOR TREATING IL-6 MEDIATED INFLAMMATION WITHOUT
IMMUNOSUPPRESSION
Abstract
The disclosure provides methods of treating inflammation without
inducing immune suppression. The method comprises administering a
therapeutically effective amount of an IL-6 antagonist at a dose
sufficient to reduce inflammation without causing immune
suppression.
Inventors: |
Devalaraja; Madhav N.;
(Acton, MA) ; Davidson; Michael H.; (Highland
Park, IL) ; Kakkar; Rahul; (Weston, MA) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Novo Nordisk A/S |
Bagsvaerd |
|
DK |
|
|
Family ID: |
1000006242520 |
Appl. No.: |
17/708660 |
Filed: |
March 30, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16396378 |
Apr 26, 2019 |
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17708660 |
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16240670 |
Jan 4, 2019 |
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16396378 |
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62614134 |
Jan 5, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 2039/55 20130101;
C07K 2317/52 20130101; A61P 13/12 20180101; A61P 19/02 20180101;
C07K 2317/76 20130101; A61P 37/02 20180101; A61K 2039/545 20130101;
A61K 2039/505 20130101; C07K 16/248 20130101 |
International
Class: |
C07K 16/24 20060101
C07K016/24; A61P 13/12 20060101 A61P013/12; A61P 37/02 20060101
A61P037/02; A61P 19/02 20060101 A61P019/02 |
Claims
1. A method of treating a patient who has KDOQI stage 3-5 chronic
kidney disease (CKD) with inflammation to reduce the risk of
cardiovascular morbidity and mortality, comprising: administering
an IL-6 antagonist to a patient with KDOQI stage 3-5 CKD and a CRP
level greater than 2 mg/L at a dose that is sufficient to reduce
the CRP level to 2 mg/L or less and reduce the risk of
cardiovascular morbidity and mortality.
2. The method of claim 1, wherein the IL-6 antagonist is
administered at a dose that is sufficient to reduce the risk of
heart failure and/or cardiovascular death.
3. The method of claim 1, wherein the IL-6 antagonist is
administered at a dose that is sufficient to reduce nonfatal
myocardial infarction and/or nonfatal stroke.
4. The method of claim 1, wherein the IL-6 antagonist is
administered at a dose that is sufficient to increase cardiac
function.
5. The method of claim 1, wherein the IL-6 antagonist is
administered at a dose that is sufficient to reduce fibrosis after
acute myocardial infarction.
6. The method of claim 1, wherein the IL-6 antagonist is
administered at a dose that does not cause immune suppression.
7. The method of claim 6, wherein the immune suppression is
measured by absolute neutrophil count (ANC).
8. The method of claim 7, wherein the post-treatment ANC is at
least 1500 cells/.mu.L.
9. The method of claim 1, wherein the post-treatment LDL level is
increased by no more than 10% as compared to pre-treatment
levels.
10. The method of claim 1, wherein the IL-6 antagonist is
administered at a monthly equivalent dose that is no more than 30%
of the monthly equivalent dose for treating rheumatoid arthritis
with the same IL-6 antagonist.
11. The method of claim 1, wherein the IL-6 antagonist is an
anti-IL-6 antibody or an anti-IL-6R antibody.
12. The method of claim 11, wherein the anti-IL-6 antibody or the
anti-IL-6R antibody is selected from the group consisting of:
COR-001, siltuximab, gerilimzumab, sirukumab, clazakizumab,
olokizumab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven
Bio), FM101 (Femta Pharmaceuticals, Lonza), tocilizumab, sarilumab,
and vobarilizumab.
13. The method of claim 12, wherein the anti-IL-6 antibody is
COR-001.
14. The method of claim 13, wherein COR-001 is administered
intravenously at a monthly equivalent dose of 2-40 mg.
15. The method of claim 13, wherein COR-001 is administered
subcutaneously at a monthly equivalent dose of 3-70 mg.
16. A method of treating a patient who has atherosclerotic
cardiovascular disease with inflammation to reduce the risk of
cardiovascular morbidity and mortality, comprising: administering
an IL-6 antagonist to a patient with atherosclerotic cardiovascular
disease and a CRP level greater than 2 mg/L at a dose that is
sufficient to reduce the CRP level to 2 mg/L or less and reduce the
risk of cardiovascular morbidity and mortality.
17. The method of claim 16, wherein the IL-6 antagonist is
administered at a dose that is sufficient to reduce the risk of
heart failure and/or cardiovascular death.
18. The method of claim 16, wherein the IL-6 antagonist is
administered at a dose that is sufficient to reduce nonfatal
myocardial infarction and/or nonfatal stroke.
19. The method of claim 16, wherein the IL-6 antagonist is
administered at a dose that is sufficient to increase cardiac
function.
20. The method of claim 16, wherein the IL-6 antagonist is
administered at a dose that is sufficient to reduce fibrosis after
acute myocardial infarction.
21. The method of claim 16, wherein the IL-6 antagonist is
administered at a dose that does not cause immune suppression.
22. The method of claim 21, wherein the immune suppression is
measured by absolute neutrophil count (ANC).
23. The method of claim 22, wherein the post-treatment ANC is at
least 1500 cells/.mu.L.
24. The method of claim 16, wherein the post-treatment LDL level is
increased by no more than 10% as compared to pre-treatment
levels.
25. The method of claim 16, wherein the IL-6 antagonist is
administered at a monthly equivalent dose that is no more than 30%
of the monthly equivalent dose for treating rheumatoid arthritis
with the same IL-6 antagonist.
26. The method of claim 16, wherein the IL-6 antagonist is an
anti-IL-6 antibody or an anti-IL-6R antibody.
27. The method of claim 26, wherein the anti-IL-6 antibody or the
anti-IL-6R antibody is selected from the group consisting of:
COR-001, siltuximab, gerilimzumab, sirukumab, clazakizumab,
olokizumab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven
Bio), FM101 (Femta Pharmaceuticals, Lonza), tocilizumab, sarilumab,
and vobarilizumab.
28. The method of claim 27, wherein the anti-IL-6 antibody is
COR-001.
29. The method of claim 28, wherein COR-001 is administered
intravenously at a monthly equivalent dose of 2-40 mg.
30. The method of claim 28, wherein COR-001 is administered
subcutaneously at a monthly equivalent dose of 3-70 mg.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending U.S.
application Ser. No. 16/396,378, filed Apr. 26, 2019, which is a
continuation of U.S. application Ser. No. 16/240,670, filed Jan. 4,
2019 (now abandoned), which claims priority to U.S. Provisional
Application No. 62/614,134, filed Jan. 5, 2018, each of which is
hereby incorporated in its entirety by reference.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which
has been submitted in ASCII format via EFS-Web and is hereby
incorporated by reference in its entirety. Said ASCII copy, created
on Mar. 9, 2022, is named 200110US04_SeqList.txt and is 27
kilobytes in size.
BACKGROUND
[0003] Chronic inflammation is a characteristic of many diseases,
including both the classical rheumatic disorders such as rheumatoid
arthritis, juvenile idiopathic arthritis, psoriatic arthritis, and
inflammatory bowel disease, as well as other systemic diseases that
are increasingly understood to be associated with chronic
inflammation, such as cardiovascular disease, renal disease,
neuroinflammatory diseases, anemias, cancer and aging.
[0004] The pro-inflammatory cytokine, IL-6, often plays a critical
role in chronic inflammation through activation of the JAK-STAT
signaling pathway, and IL-6 inhibitors have been developed to treat
certain inflammatory disorders in which IL-6 has been shown to
contribute significantly to disease etiology. The anti-IL-6
receptor antibody, tocilizumab (ACTEMRA), has been approved for
treatment of rheumatoid arthritis, giant cell arteritis,
polyarticular juvenile idiopathic arthritis, systemic juvenile
idiopathic arthritis, and iatrogenic cytokine release syndrome. The
anti-IL-6 receptor antibody, sarilumab (KEVZARA), has been approved
to treat adult patients with moderately to severely active
rheumatoid arthritis.
[0005] Although inhibition of IL-6 can be effective, treatment of
chronic inflammation with IL-6 inhibitors using current dose
regimens often leads to immune suppression. Immunosuppression can
result in increased susceptibility to pathogens such as bacteria,
fungi, and viruses. The FDA-approved product label for ACTEMRA
warns of the risk of serious infections leading to hospitalization
or death, including tuberculosis, bacterial, invasive fungal,
viral, and other opportunistic infection; the KEVZARA label warns
of serious infections leading to hospitalization or death including
bacterial, viral, invasive fungal, and other opportunistic
infections.
[0006] There is, therefore, a need for new methods for treating
IL-6 mediated inflammation that do not lead to immune
suppression.
SUMMARY
[0007] We have demonstrated that IL-6 antagonists can be
administered at a dose, on a schedule, and for a period sufficient
to reduce inflammation without causing immune suppression.
[0008] Accordingly, in a first aspect, methods for treating
IL-6-mediated inflammation in a patient are provided. The methods
comprise: administering an IL-6 antagonist to a patient with
IL-6-mediated inflammation at a dose that is sufficient to reduce
inflammation without causing immune suppression.
[0009] In some embodiments, the patient has an elevated
pre-treatment C-reactive protein (CRP) level. In some embodiments,
the pre-treatment CRP level of the patient is at least 2 mg/L. In
some embodiments, the pre-treatment CRP level of the patient is at
least 4 mg/L. In some embodiments, the pre-treatment CRP level of
the patient is at least 6 mg/L. In some embodiments, the
pre-treatment CRP level of the patient is at least 10 mg/L.
[0010] In some embodiments, the patient has an elevated
pre-treatment serum IL-6 level. In some embodiments, the
pre-treatment serum IL-6 level of the patient is at least 4 pg/mL.
In some embodiments, the pre-treatment serum IL-6 level of the
patient is at least 4 pg/mL. In some embodiments, the pre-treatment
serum IL-6 level of the patient is at least 5 pg/mL. In some
embodiments, the pre-treatment serum IL-6 level of the patient is
at least 10 pg/mL.
[0011] In some embodiments, the inflammation is measured by the
level of C-reactive protein (CRP). In some embodiments, the
post-treatment CRP level is no more than 2 mg/L. In some
embodiments, the post-treatment CRP level is no more than 1 mg/L.
In some embodiments, the CRP level is decreased by at least 50% as
compared to pre-treatment levels. In some embodiments, the CRP
level is decreased by at least 70% as compared to pre-treatment
levels. In some embodiments, the CRP level is decreased by at least
80% as compared to pre-treatment levels. In some embodiments, the
CRP level is decreased by at least 90% as compared to pre-treatment
levels.
[0012] In some embodiments, the immune suppression is measured by
absolute neutrophil count (ANC). In some embodiments, the
post-treatment ANC is at least 500 cells/.mu.L. In some
embodiments, the post-treatment ANC is at least 1000 cells/.mu.L.
In some embodiments, the post-treatment ANC is at least 1500
cells/.mu.L. In some embodiments, the post-treatment ANC is at
least 2000 cells/.mu.L. In some embodiments, the ANC is decreased
by no more than 2000 cells/.mu.L as compared to pre-treatment
levels. In some embodiments, the ANC is decreased by no more than
1500 cells/.mu.L as compared to pre-treatment levels. In some
embodiments, the ANC is decreased by no more than 1000 cells/.mu.L
as compared to pre-treatment levels. In some embodiments, the ANC
is decreased by no more than 500 cells/.mu.L as compared to
pre-treatment levels. In some embodiments, the ANC is decreased by
no more than 50% as compared to pre-treatment levels. In some
embodiments, the ANC is decreased by no more than 40% as compared
to pre-treatment levels. In some embodiments, the ANC is decreased
by no more than 30% as compared to pre-treatment levels. In some
embodiments, the ANC is decreased by no more than 20% as compared
to pre-treatment levels. In some embodiments, the ANC is decreased
by no more than 10% as compared to pre-treatment levels. In some
embodiments, the ANC is not decreased as compared to pre-treatment
levels.
[0013] In some embodiments, the IL-6 antagonist is administered at
a monthly equivalent dose that is no more than 30% of the monthly
equivalent dose for treating rheumatoid arthritis with the same
IL-6 antagonist. In some embodiments, the IL-6 antagonist is
administered at a monthly equivalent dose that is no more than 20%
of the monthly equivalent dose for treating rheumatoid arthritis
with the same IL-6 antagonist. In some embodiments, the IL-6
antagonist is administered at a monthly equivalent dose that is no
more than 10% of the monthly equivalent dose for treating
rheumatoid arthritis with the same IL-6 antagonist. In some
embodiments, the IL-6 antagonist is administered at a monthly
equivalent dose that is about 25% of a monthly equivalent dose for
treating rheumatoid arthritis with the same IL-6 antagonist. In
some embodiments, the IL-6 antagonist is administered at a monthly
equivalent dose that is about 20% of a monthly equivalent dose for
treating rheumatoid arthritis with the same IL-6 antagonist. In
some embodiments, the IL-6 antagonist is administered at a monthly
equivalent dose that is about 15% of a monthly equivalent dose for
treating rheumatoid arthritis with the same IL-6 antagonist. In
some embodiments, the IL-6 antagonist is administered at a monthly
equivalent dose that is about 10% of a monthly equivalent dose for
treating rheumatoid arthritis with the same IL-6 antagonist. In
some embodiments, the IL-6 antagonist is administered at a monthly
equivalent dose that is about 5% of a monthly equivalent dose for
treating rheumatoid arthritis with the same IL-6 antagonist.
[0014] In some embodiments, the IL-6 antagonist is an anti-IL-6
antibody.
[0015] In some embodiments, the anti-IL-6 antibody is COR-001. In
some embodiments, COR-001 is administered intravenously at a
monthly equivalent dose of 2-40 mg. In some embodiments, COR-001 is
administered intravenously at a monthly equivalent dose of about 2
mg. In some embodiments, COR-001 is administered intravenously at a
monthly equivalent dose of about 4 mg. In some embodiments, COR-001
is administered intravenously at a monthly equivalent dose of about
6 mg. In some embodiments, COR-001 is administered intravenously at
a monthly equivalent dose of about 10 mg. In some embodiments,
COR-001 is administered intravenously at a monthly equivalent dose
of about 20 mg. In some embodiments, COR-001 is administered
intravenously at a monthly equivalent dose of about 40 mg. In some
embodiments, COR-001 is administered subcutaneously at a monthly
equivalent dose of 3-70 mg. In some embodiments, COR-001 is
administered subcutaneously at a monthly equivalent dose of about 3
mg. In some embodiments, COR-001 is administered subcutaneously at
a monthly equivalent dose of about 7 mg. In some embodiments,
COR-001 is administered subcutaneously at a monthly equivalent dose
of about 10 mg. In some embodiments, COR-001 is administered
subcutaneously at a monthly equivalent dose of about 17 mg. In some
embodiments, COR-001 is administered subcutaneously at a monthly
equivalent dose of about 35 mg. In some embodiments, COR-001 is
administered subcutaneously at a monthly equivalent dose of about
70 mg.
[0016] In some embodiments, the anti-IL-6 antibody is siltuximab.
In some embodiments, siltuximab is administered intravenously at a
monthly equivalent dose of 50-500 mg. In some embodiments,
siltuximab is administered intravenously at a monthly equivalent
dose of about 50 mg. In some embodiments, siltuximab is
administered intravenously at a monthly equivalent dose of about
100 mg. In some embodiments, siltuximab is administered
intravenously at a monthly equivalent dose of about 150 mg. In some
embodiments, siltuximab is administered intravenously at a monthly
equivalent dose of about 200 mg. In some embodiments, siltuximab is
administered intravenously at a monthly equivalent dose of about
300 mg. In some embodiments, siltuximab is administered
intravenously at a monthly equivalent dose of about 500 mg. In some
embodiments, siltuximab is administered subcutaneously at a monthly
equivalent dose of 80-800 mg. In some embodiments, siltuximab is
administered subcutaneously at a monthly equivalent dose of about
80 mg. In some embodiments, siltuximab is administered
subcutaneously at a monthly equivalent dose of about 160 mg. In
some embodiments, siltuximab is administered subcutaneously at a
monthly equivalent dose of about 240 mg. In some embodiments,
siltuximab is administered subcutaneously at a monthly equivalent
dose of about 320 mg. In some embodiments, siltuximab is
administered subcutaneously at a monthly equivalent dose of about
480 mg. In some embodiments, siltuximab is administered
subcutaneously at a monthly equivalent dose of about 800 mg.
[0017] In some embodiments, the anti-IL-6 antibody is gerilimzumab.
In some embodiments, gerilimzumab is administered intravenously at
a monthly equivalent dose of 0.075-1.8 mg. In some embodiments,
gerilimzumab is administered intravenously at a monthly equivalent
dose of about 0.075 mg. In some embodiments, gerilimzumab is
administered intravenously at a monthly equivalent dose of about
0.12 mg. In some embodiments, gerilimzumab is administered
intravenously at a monthly equivalent dose of about 0.3 mg. In some
embodiments, gerilimzumab is administered intravenously at a
monthly equivalent dose of about 0.6 mg. In some embodiments,
gerilimzumab is administered intravenously at a monthly equivalent
dose of about 0.9 mg. In some embodiments, gerilimzumab is
administered intravenously at a monthly equivalent dose of about
1.8 mg. In some embodiments, gerilimzumab is administered
subcutaneously at a monthly equivalent dose of 0.125-3 mg. In some
embodiments, gerilimzumab is administered subcutaneously at a
monthly equivalent dose of about 0.125 mg. In some embodiments,
gerilimzumab is administered subcutaneously at a monthly equivalent
dose of about 0.2 mg. In some embodiments, gerilimzumab is
administered subcutaneously at a monthly equivalent dose of about
0.5 mg. In some embodiments, gerilimzumab is administered
subcutaneously at a monthly equivalent dose of about 1 mg. In some
embodiments, gerilimzumab is administered subcutaneously at a
monthly equivalent dose of about 1.5 mg. In some embodiments,
gerilimzumab is administered subcutaneously at a monthly equivalent
dose of about 3 mg.
[0018] In some embodiments, the anti-IL-6 antibody is sirukumab. In
some embodiments, sirukumab is administered intravenously at a
monthly equivalent dose of 1.5-60 mg. In some embodiments,
sirukumab is administered intravenously at a monthly equivalent
dose of about 1.5 mg. In some embodiments, sirukumab is
administered intravenously at a monthly equivalent dose of about 3
mg. In some embodiments, sirukumab is administered intravenously at
a monthly equivalent dose of about 6 mg. In some embodiments,
sirukumab is administered intravenously at a monthly equivalent
dose of about 12 mg. In some embodiments, sirukumab is administered
intravenously at a monthly equivalent dose of about 36 mg. In some
embodiments, sirukumab is administered intravenously at a monthly
equivalent dose of about 60 mg. In some embodiments, sirukumab is
administered subcutaneously at a monthly equivalent dose of 2.5-100
mg. In some embodiments, sirukumab is administered subcutaneously
at a monthly equivalent dose of about 2.5 mg. In some embodiments,
sirukumab is administered subcutaneously at a monthly equivalent
dose of about 5 mg. In some embodiments, sirukumab is administered
subcutaneously at a monthly equivalent dose of about 10 mg. In some
embodiments, sirukumab is administered subcutaneously at a monthly
equivalent dose of about 20 mg. In some embodiments, sirukumab is
administered subcutaneously at a monthly equivalent dose of about
60 mg. In some embodiments, sirukumab is administered
subcutaneously at a monthly equivalent dose of about 100 mg.
[0019] In some embodiments, the anti-IL-6 antibody is clazakizumab.
In some embodiments, clazakizumab is administered intravenously at
a monthly equivalent dose of 3-60 mg. In some embodiments,
clazakizumab is administered intravenously at a monthly equivalent
dose of about 3 mg. In some embodiments, clazakizumab is
administered intravenously at a monthly equivalent dose of about 6
mg. In some embodiments, clazakizumab is administered intravenously
at a monthly equivalent dose of about 12 mg. In some embodiments,
clazakizumab is administered intravenously at a monthly equivalent
dose of about 24 mg. In some embodiments, clazakizumab is
administered intravenously at a monthly equivalent dose of about 36
mg. In some embodiments, clazakizumab is administered intravenously
at a monthly equivalent dose of about 60 mg. In some embodiments,
clazakizumab is administered subcutaneously at a monthly equivalent
dose of 5-100 mg. In some embodiments, clazakizumab is administered
subcutaneously at a monthly equivalent dose of about 5 mg. In some
embodiments, clazakizumab is administered subcutaneously at a
monthly equivalent dose of about 10 mg. In some embodiments,
clazakizumab is administered subcutaneously at a monthly equivalent
dose of about 20 mg. In some embodiments, clazakizumab is
administered subcutaneously at a monthly equivalent dose of about
40 mg. In some embodiments, clazakizumab is administered
subcutaneously at a monthly equivalent dose of about 60 mg. In some
embodiments, clazakizumab is administered subcutaneously at a
monthly equivalent dose of about 100 mg.
[0020] In some embodiments, the anti-IL-6 antibody is olokizumab.
In some embodiments, olokizumab is administered intravenously at a
monthly equivalent dose of 1.8-60 mg. In some embodiments,
olokizumab is administered intravenously at a monthly equivalent
dose of about 1.8 mg. In some embodiments, olokizumab is
administered intravenously at a monthly equivalent dose of about
3.6 mg. In some embodiments, olokizumab is administered
intravenously at a monthly equivalent dose of about 9 mg. In some
embodiments, olokizumab is administered intravenously at a monthly
equivalent dose of about 18 mg. In some embodiments, olokizumab is
administered intravenously at a monthly equivalent dose of about 45
mg. In some embodiments, olokizumab is administered intravenously
at a monthly equivalent dose of about 60 mg. In some embodiments,
olokizumab is administered subcutaneously at a monthly equivalent
dose of 3-100 mg. In some embodiments, olokizumab is administered
subcutaneously at a monthly equivalent dose of about 3 mg. In some
embodiments, olokizumab is administered subcutaneously at a monthly
equivalent dose of about 6 mg. In some embodiments, olokizumab is
administered subcutaneously at a monthly equivalent dose of about
15 mg. In some embodiments, olokizumab is administered
subcutaneously at a monthly equivalent dose of about 30 mg. In some
embodiments, olokizumab is administered subcutaneously at a monthly
equivalent dose of about 72 mg. In some embodiments, olokizumab is
administered subcutaneously at a monthly equivalent dose of about
100 mg.
[0021] In some embodiments, the anti-IL-6 antibody is VX30
(VOP-R003; Vaccinex). In some embodiments, VX30 (VOP-R003;
Vaccinex) is administered intravenously. In some embodiments, VX30
(VOP-R003; Vaccinex) is administered subcutaneously.
[0022] In some embodiments, the anti-IL-6 antibody is EB-007
(EBI-029; Eleven Bio). In some embodiments, EB-007 (EBI-029; Eleven
Bio) is administered intravenously. In some embodiments, EB-007
(EBI-029; Eleven Bio) is administered subcutaneously.
[0023] In some embodiments, the anti-IL-6 antibody is FM101 (Femta
Pharmaceuticals, Lonza). In some embodiments, FM101 (Femta
Pharmaceuticals, Lonza) is administered intravenously. In some
embodiments, FM101 (Femta Pharmaceuticals, Lonza) is administered
subcutaneously.
[0024] In some embodiments, the IL-6 antagonist is an anti-IL-6R
antibody.
[0025] In some embodiments, the anti-IL-6R antibody is tocilizumab.
In some embodiments, tocilizumab is administered intravenously at a
monthly equivalent dose of 50-500 mg. In some embodiments,
tocilizumab is administered intravenously at a monthly equivalent
dose of about 50 mg. In some embodiments, tocilizumab is
administered intravenously at a monthly equivalent dose of about
100 mg. In some embodiments, tocilizumab is administered
intravenously at a monthly equivalent dose of about 150 mg. In some
embodiments, tocilizumab is administered intravenously at a monthly
equivalent dose of about 250 mg. In some embodiments, tocilizumab
is administered intravenously at a monthly equivalent dose of about
350 mg. In some embodiments, tocilizumab is administered
intravenously at a monthly equivalent dose of about 500 mg. In some
embodiments, tocilizumab is administered subcutaneously at a
monthly equivalent dose of 80-800 mg. In some embodiments,
tocilizumab is administered subcutaneously at a monthly equivalent
dose of about 80 mg. In some embodiments, tocilizumab is
administered subcutaneously at a monthly equivalent dose of about
160 mg. In some embodiments, tocilizumab is administered
subcutaneously at a monthly equivalent dose of about 240 mg. In
some embodiments, tocilizumab is administered subcutaneously at a
monthly equivalent dose of about 400 mg. In some embodiments,
tocilizumab is administered subcutaneously at a monthly equivalent
dose of about 560 mg. In some embodiments, tocilizumab is
administered subcutaneously at a monthly equivalent dose of about
800 mg.
[0026] In some embodiments, the anti-IL-6R antibody is sarilumab.
In some embodiments, sarilumab is administered intravenously at a
monthly equivalent dose of 12-120 mg. In some embodiments,
sarilumab is administered intravenously at a monthly equivalent
dose of about 12 mg. In some embodiments, sarilumab is administered
intravenously at a monthly equivalent dose of about 24 mg. In some
embodiments, sarilumab is administered intravenously at a monthly
equivalent dose of about 48 mg. In some embodiments, sarilumab is
administered intravenously at a monthly equivalent dose of about 60
mg. In some embodiments, sarilumab is administered intravenously at
a monthly equivalent dose of about 72 mg. In some embodiments,
sarilumab is administered intravenously at a monthly equivalent
dose of about 120 mg. In some embodiments, sarilumab is
administered subcutaneously at a monthly equivalent dose of 20-200
mg. In some embodiments, sarilumab is administered subcutaneously
at a monthly equivalent dose of about 20 mg. In some embodiments,
sarilumab is administered subcutaneously at a monthly equivalent
dose of about 40 mg. In some embodiments, sarilumab is administered
subcutaneously at a monthly equivalent dose of about 80 mg. In some
embodiments, sarilumab is administered subcutaneously at a monthly
equivalent dose of about 100 mg. In some embodiments, sarilumab is
administered subcutaneously at a monthly equivalent dose of about
120 mg. In some embodiments, sarilumab is administered
subcutaneously at a monthly equivalent dose of about 200 mg.
[0027] In some embodiments, the anti-IL-6R antibody is
vobarilizumab. In some embodiments, vobarilizumab is administered
intravenously at a monthly equivalent dose of 4-120 mg. In some
embodiments, vobarilizumab is administered intravenously at a
monthly equivalent dose of about 4 mg. In some embodiments,
vobarilizumab is administered intravenously at a monthly equivalent
dose of about 6 mg. In some embodiments, vobarilizumab is
administered intravenously at a monthly equivalent dose of about 30
mg. In some embodiments, vobarilizumab is administered
intravenously at a monthly equivalent dose of about 60 mg. In some
embodiments, vobarilizumab is administered intravenously at a
monthly equivalent dose of about 84 mg. In some embodiments,
vobarilizumab is administered intravenously at a monthly equivalent
dose of about 120 mg. In some embodiments, vobarilizumab is
administered subcutaneously at a monthly equivalent dose of 7-200
mg. In some embodiments, vobarilizumab is administered
subcutaneously at a monthly equivalent dose of about 7 mg. In some
embodiments, vobarilizumab is administered subcutaneously at a
monthly equivalent dose of about 10 mg. In some embodiments,
vobarilizumab is administered subcutaneously at a monthly
equivalent dose of about 50 mg. In some embodiments, vobarilizumab
is administered subcutaneously at a monthly equivalent dose of
about 100 mg. In some embodiments, vobarilizumab is administered
subcutaneously at a monthly equivalent dose of about 140 mg. In
some embodiments, vobarilizumab is administered subcutaneously at a
monthly equivalent dose of about 200 mg.
[0028] In some embodiments, the IL-6 antagonist is a JAK inhibitor.
In some embodiments, the IL-6 antagonist is a STAT3 inhibitor.
[0029] In some embodiments, the patient has a hepcidin-mediated
disorder.
[0030] In some embodiments, the patient has kidney disease. In some
embodiments, the patient has chronic kidney disease. In some
embodiments, the patient has KDOQI stage 1-5 chronic kidney
disease. In some embodiments, the patient has KDOQI stage 3-5
chronic kidney disease. In some embodiments, the patient is not on
dialysis. In some embodiments, the patient has KDOQI stage 5
chronic kidney disease. In some embodiments, the patient is on
dialysis. In some embodiments, the patient has cardiorenal syndrome
(CRS). In some embodiments, the patient has CRS Type 4.
[0031] In some embodiments, the patient has cardiovascular disease.
In some embodiments, the patient has diuretic resistant heart
failure. In some embodiments, the patient has congestive heart
failure (CHF). In some embodiments, the patient has congestive
heart failure (CHF) with reduced ejection fraction. In some
embodiments, the patient has congestive heart failure (CHF) with
mid-range ejection fraction. In some embodiments, the patient has
congestive heart failure (CHF) with preserved ejection fraction. In
some embodiments, the patient has acute coronary syndrome. In some
embodiments, the patient has atherosclerosis.
[0032] In some embodiments, the patient has anemia. In some
embodiments, the patient has anemia of chronic disease. In some
embodiments, the patient has iron-refractory iron-deficiency anemia
(IRIDA).
[0033] In some embodiments, the patient has diabetes. In some
embodiments, the patient has type II diabetes. In some embodiments,
the patient has insulin-resistant diabetes.
[0034] In some embodiments, the patient has liver disease. In some
embodiments, the patient has non-alcoholic steatohepatitis
(NASH).
[0035] In some embodiments, the patient has osteoporosis.
[0036] In some embodiments, the patient has depression.
[0037] In some embodiments, the patient has asthma.
[0038] In some embodiments, the patient has neuroinflammatory
disorder. In some embodiments, the patient has Alzheimer's disease.
In some embodiments, the patient has Parkinson's disease. In some
embodiments, the patient has multiple sclerosis. In some
embodiments, the patient has amyotrophic lateral sclerosis
(ALS).
[0039] In some embodiments, the patient has age-related macular
degeneration (AMD).
[0040] In some embodiments, the patient has cancer. In some
embodiments, the cancer is selected from the group consisting of:
solid tumors, small cell lung cancer, non-small cell lung cancer,
hematological cancer, multiple myeloma, leukemia, chronic
lymphocytic leukemia (CLL), chronic myeloid leukemia (CML),
lymphomas, Hodgkin's lymphoma and hepatic adenoma.
[0041] In some embodiments, patient has skin disease.
[0042] In some embodiments, the method prevents aging in the
patient.
[0043] In another aspect, methods for treating inflammation in a
patient with cardiovascular disease are provided herein. The
methods comprise: administering an IL-6 antagonist to a patient
with cardiovascular disease and CRP level greater than 2 mg/L at a
dose that is sufficient to reduce CRP levels to 2 mg/L or less
without causing neutropenia.
[0044] In some embodiments, the IL-6 antagonist is administered at
a monthly equivalent dose that is no more than 30% of the monthly
equivalent dose for treating rheumatoid arthritis with the same
IL-6 antagonist. In some embodiments, the IL-6 antagonist is
administered at a monthly equivalent dose that is no more than 20%
of the monthly equivalent dose for treating rheumatoid arthritis
with the same IL-6 antagonist. In some embodiments, the IL-6
antagonist is administered at a monthly equivalent dose that is no
more than 10% of the monthly equivalent dose for treating
rheumatoid arthritis with the same IL-6 antagonist.
[0045] In another aspect, methods for treating inflammation in a
patient with chronic kidney disease (CKD) are provided herein. The
methods comprise: administering an IL-6 antagonist to a patient
with CKD and a CRP level greater than 2 mg/L at a dose that is
sufficient to reduce CRP levels to 2 mg/L or less without causing
neutropenia.
[0046] In some embodiments, the IL-6 antagonist is administered at
a monthly equivalent dose that is no more than 30% of the monthly
equivalent dose for treating rheumatoid arthritis with the same
IL-6 antagonist. In some embodiments, the IL-6 antagonist is
administered at a monthly equivalent dose that is no more than 20%
of the monthly equivalent dose for treating rheumatoid arthritis
with the same IL-6 antagonist. In some embodiments, the IL-6
antagonist is administered at a monthly equivalent dose that is no
more than 10% of the monthly equivalent dose for treating
rheumatoid arthritis with the same IL-6 antagonist.
BRIEF DESCRIPTION OF THE DRAWINGS
[0047] These and other features, aspects, and advantages of the
present invention will become better understood with regard to the
following description, and accompanying drawings, where:
[0048] FIG. 1 presents the dose escalation schematic for the phase
1/phase 2 randomized, double-blind, placebo-controlled trial of
COR-001 in hemodialysis patients described in Example 1.
[0049] FIG. 2 shows the timeline and the efficacy analysis of the
treatment phase and the safety follow-up phase.
[0050] FIGS. 3A and 3B show the results of C-reactive protein (CRP)
responder analysis after treatment with COR-001 (anti-IL-6) or
canakinumab (anti-IL1(3). FIG. 3A shows the C-reactive protein
responder rate after intravenous treatment with COR-001 in patients
with stage 5 chronic kidney disease who were on dialysis in the
clinical trial described in Example 1. The baseline hsCRP was 12.4
mg/L. Responder was defined as Week 12 average hsCRP <2 mg/L.
FIG. 3B shows the C-reactive protein responder rate after treatment
with canakinumab in the CANTOS trial, as described in the research
literature. The baseline hsCRP was 5.5 mg/L. Responder was defined
as 3-month hsCRP <2 mg/L.
[0051] FIG. 4 shows the results of hemoglobin responder analysis
after treatment with COR-001 at doses of 2 mg, 6 mg, and 20 mg.
Hemoglobin responder was defined as increase by 1 g/dL or more
after Day 29. Investigators were not permitted to change ESA dosing
until after Day 29.
[0052] FIG. 5 shows the effect of COR-001 on the diastolic cardiac
parameter, NT-proBNP.
[0053] FIGS. 6A and 6B show the adverse responder rate for
neutrophils and platelets. FIG. 6A shows the neutrophils adverse
responder rate. An Adverse Responder was defined as Week 12 average
neutrophils <2.times.10.sup.6/mL. FIG. 6B shows the platelets
adverse responder rate. Adverse responder was defined as Week 12
average platelets <100.times.10.sup.6/mL.
DETAILED DESCRIPTION
1. Definitions
[0054] Unless defined otherwise, all technical and scientific terms
used herein have the meaning commonly understood by one of ordinary
skill in the art to which the invention pertains.
[0055] As used herein, "interleukin 6 (IL-6)" or "IL-6 polypeptide"
refers to a polypeptide or fragment thereof having at least about
85% or greater amino acid identity to the amino acid sequence
provided at NCBI Accession No. NP_000591 and having IL-6 biological
activity. IL-6 is a pleotropic cytokine with multiple biologic
functions. Exemplary IL-6 biological activities include
immunostimulatory and pro-inflammatory activities. An exemplary
IL-6 amino acid sequence is provided below:
TABLE-US-00001 (SEQ ID NO: 1) 1 MCVGARRLGR GPCAALLLLG LGLSTVTGLH
CVGDTYPSND RCCHECRPGN GMVSRCSRSQ 61 NTVCRPCGPG FYNDVVSSKP
CKPCTWCNLR SGSERKQLCT ATQDTVCRCR AGTQPLDSYK 121 PGVDCAPCPP
GHFSPGDNQA CKPWTNCTLA GKHTLQPASN SSDAICEDRD PPATQPQETQ 181
GPPARPITVQ PTEAWPRTSQ GPSTRPVEVP GGRAVAAILG LGLVLGLLGP LAILLALYLL
241 RRDQRLPPDA HKPPGGGSFR TPIQEEQADA HSTLAKI
[0056] As used herein, "interleukin 6 (IL-6) nucleic acid" refers
to a polynucleotide encoding an interleukin 6 (IL-6) polypeptide.
An exemplary interleukin 6 (IL-6) nucleic acid sequence is provided
at NCBI Accession No. NM_000600. The exemplary sequence at NCBI
Accession No. NM_000600 is provided below:
TABLE-US-00002 (SEQ ID NO: 2) 1 AATATTAGAG TCTCAACCCC CAATAAATAT
AGGACTGGAG ATGTCTGAGG CTCATTCTGC 61 CCTCGAGCCC ACCGGGAACG
AAAGAGAAGC TCTATCTCCC CTCCAGGAGC CCAGCTATGA 121 ACTCCTTCTC
CACAAGCGCC TTCGGTCCAG TTGCCTTCTC CCTGGGGCTG CTCCTGGTGT 181
TGCCTGCTGC CTTCCCTGCC CCAGTACCCC CAGGAGAAGA TTCCAAAGAT GTAGCCGCCC
241 CACACAGACA GCCACTCACC TCTTCAGAAC GAATTGACAA ACAAATTCGG
TACATCCTCG 301 ACGGCATCTC AGCCCTGAGA AAGGAGACAT GTAACAAGAG
TAACATGTGT GAAAGCAGCA 361 AAGAGGCACT GGCAGAAAAC AACCTGAACC
TTCCAAAGAT GGCTGAAAAA GATGGATGCT 421 TCCAATCTGG ATTCAATGAG
GAGACTTGCC TGGTGAAAAT CATCACTGGT CTTTTGGAGT 481 TTGAGGTATA
CCTAGAGTAC CTCCAGAACA GATTTGAGAG TAGTGAGGAA CAAGCCAGAG 541
CTGTGCAGAT GAGTACAAAA GTCCTGATCC AGTTCCTGCA GAAAAAGGCA AAGAATCTAG
601 ATGCAATAAC CACCCCTGAC CCAACCACAA ATGCCAGCCT GCTGACGAAG
CTGCAGGCAC 661 AGAACCAGTG GCTGCAGGAC ATGACAACTC ATCTCATTCT
GCGCAGCTTT AAGGAGTTCC 721 TGCAGTCCAG CCTGAGGGCT CTTCGGCAAA
TGTAGCATGG GCACCTCAGA TTGTTGTTGT 781 TAATGGGCAT TCCTTCTTCT
GGTCAGAAAC CTGTCCACTG GGCACAGAAC TTATGTTGTT 841 CTCTATGGAG
AACTAAAAGT ATGAGCGTTA GGACACTATT TTAATTATTT TTAATTTATT 901
AATATTTAAA TATGTGAAGC TGAGTTAATT TATGTAAGTC ATATTTATAT TTTTAAGAAG
961 TACCACTTGA AACATTTTAT GTATTAGTTT TGAAATAATA ATGGAAAGTG
GCTATGCAGT 1021 TTGAATATCC TTTGTTTCAG AGCCAGATCA TTTCTTGGAA
AGTGTAGGCT TACCTCAAAT 1081 AAATGGCTAA CTTATACATA TTTTTAAAGA
AATATTTATA TTGTATTTAT ATAATGTATA 1141 AATGGTTTTT ATACCAATAA
ATGGCATTTT AAAAAATTCA GCAAAAAAAA AAAAAAAAAA 1201 A
[0057] As used herein, "interleukin 6 receptor (IL-6R) complex"
refers to a protein complex comprising an IL-6 receptor subunit
alpha (IL-6R.alpha.) and interleukin 6 signal transducer
glycoprotein 130 (gp130), also termed interleukin 6 receptor
subunit .beta. (IL-6R.beta.).
[0058] As used herein, "interleukin 6 receptor subunit .alpha.
(IL-6R.alpha.) polypeptide" refers to a polypeptide or fragment
thereof having at least about 85% or greater amino acid identity to
the amino acid sequence provided at NCBI Accession No. NP_000556 or
NP_852004 and having IL-6 receptor biological activity. Exemplary
IL-6R.alpha. biological activities include binding to IL-6, binding
to glycoprotein 130 (gp130), and regulation of cell growth and
differentiation. An exemplary IL-6R sequence is provided below:
TABLE-US-00003 (SEQ ID NO: 3) 1 MLAVGCALLA ALLAAPGAAL APRRCPAQEV
ARGVLTSLPG DSVTLTCPGV EPEDNATVHW 61 VLRKPAAGSH PSRWAGMGRR
LLLRSVQLHD SGNYSCYRAG RPAGTVHLLV DVPPEEPQLS 121 CFRKSPLSNV
VCEWGPRSTP SLTTKAVLLV RKFQNSPAED FQEPCQYSQE SQKFSCQLAV 181
PEGDSSFYIV SMCVASSVGS KFSKTQTFQG CGILQPDPPA NITVTAVARN PRWLSVTWQD
241 PHSWNSSFYR LRFELRYRAE RSKTFTTWMV KDLQHHCVIH DAWSGLRHVV
QLRAQEEFGQ 301 GEWSEWSPEA MGTPWTESRS PPAENEVSTP MQALTTNKDD
DNILFRDSAN ATSLPVQDSS 361 SVPLPTFLVA GGSLAFGTLL CIAIVLRFKK
TWKLRALKEG KTSMHPPYSL GQLVPERPRP 421 TPVLVPLISP PVSPSSLGSD
NTSSHNRPDA RDPRSPYDIS NTDYFFPR
[0059] As used herein, "glycoprotein 130 (gp130)" or "interleukin 6
receptor subunit .beta. (IL-6R.beta.) polypeptide" refers to a
polypeptide or fragment thereof having at least about 85% or
greater amino acid identity to the amino acid sequence provided at
NCBI Accession No. NP_002175, NP_786943, or NP_001177910 and having
IL-6 receptor biological activity. Exemplary IL-6R.beta. biological
activities include binding to IL-6R.alpha., IL-6 receptor signaling
activity, and regulation of cell growth, differentiation, hepcidin
expression etc. An exemplary IL-6R.beta. sequence is provided
below:
TABLE-US-00004 (SEQ ID NO: 4) 1 MLTLQTWLVQ ALFIFLTTES TGELLDPCGY
ISPESPVVQL HSNFTAVCVL KEKCMDYFHV 61 NANYIVWKTN HFTIPKEQYT
IINRTASSVT FTDIASLNIQ LTCNILTFGQ LEQNVYGITI 121 ISGLPPEKPK
NLSCIVNEGK KMRCEWDGGR ETHLETNFTL KSEWATHKFA DCKAKRDTPT 181
SCTVDYSTVY FVNIEVWVEA ENALGKVTSD HINFDPVYKV KPNPPHNLSV INSEELSSIL
241 KLTWTNPSIK SVIILKYNIQ YRTKDASTWS QIPPEDTAST RSSFTVQDLK
PFTEYVFRIR 301 CMKEDGKGYW SDWSEEASGI TYEDRPSKAP SFWYKIDPSH
TQGYRTVQLV WKTLPPFEAN 361 GKILDYEVTL TRWKSHLQNY TVNATKLTVN
LTNDRYLATL TVRNLVGKSD AAVLTIPACD 421 FQATHPVMDL KAFPKDNMLW
VEWTTPRESV KKYILEWCVL SDKAPCITDW QQEDGTVHRT 481 YLRGNLAESK
CYLITVTPVY ADGPGSPESI KAYLKQAPPS KGPTVRTKKV GKNEAVLEWD 541
QLPVDVQNGF IRNYTIFYRT IIGNETAVNV DSSHTEYTLS SLTSDTLYMV RMAAYTDEGG
601 KDGPEFTFTT PKFAQGEIEA IVVPVCLAFL LTTLLGVLFC FNKRDLIKKH
IWPNVPDPSK 661 SHIAQWSPHT PPRHNFNSKD QMYSDGNFTD VSVVEIEAND
KKPFPEDLKS LDLFKKEKIN 721 TEGHSSGIGG SSCMSSSRPS ISSSDENESS
QNTSSTVQYS TVVHSGYRHQ VPSVQVFSRS 781 ESTQPLLDSE ERPEDLQLVD
HVDGGDGILP RQQYFKQNCS QHESSPDISH FERSKQVSSV 841 NEEDFVRLKQ
QISDHISQSC GSGQMKMFQE VSAADAFGPG TEGQVERFET VGMEAATDEG 901
MPKSYLPQTV RQGGYMPQ
[0060] Unless otherwise specified, "IL-6 antagonist" refers an
agent that is capable of decreasing the biological activity of
IL-6. IL-6 antagonists include agents that decrease the level of
IL-6 polypeptide in serum, including agents that decrease the
expression of an IL-6 polypeptide or nucleic acid; agents that
decrease the ability of IL-6 to bind to the IL-6R; agents that
decrease the expression of the IL-6R; and agents that decrease
signal transduction by the IL-6R receptor when bound by IL-6. In
preferred embodiments, the IL-6 antagonist decreases IL-6
biological activity by at least about 10%, 20%, 30%, 50%, 70%, 80%,
90%, 95%, or even 100%. As further described below, IL-6
antagonists include IL-6 binding polypeptides, such as anti-IL-6
antibodies and antigen binding fragments or derivatives thereof;
IL-6R binding polypeptides, such as anti-IL-6R antibodies and
antigen binding fragments or derivatives thereof; and synthetic
chemical molecules, such as JAK1 and JAK3 inhibitors.
[0061] The term "IL-6 antibody" or "anti-IL-6 antibody" refers to
an antibody that specifically binds IL-6. Anti-IL-6 antibodies
include monoclonal and polyclonal antibodies that are specific for
IL-6, and antigen-binding fragments or derivatives thereof. IL-6
antibodies are described in greater detail below.
[0062] As used herein, the term "IL-6 mediated inflammation" or
"IL-6 mediated inflammatory disorder" refers to inflammation or
inflammation related disorder in which IL-6 is known or suspected
to contribute to the etiology or symptoms of the inflammation.
[0063] The term "C-reactive protein" or "CRP" refers to a
polypeptide or fragment thereof having at least about 85% or
greater amino acid identity to the amino acid sequence provided at
NCBI Accession No. NP_000558 and having complement activating
activity. CRP levels increase in response to inflammation, and can
be measured with an hsCRP (high-sensitivity C-reactive protein)
test. An exemplary CRP sequence is provided below:
TABLE-US-00005 (SEQ ID NO: 5) 1 MEKLLCFLVL TSLSHAFGQT DMSRKAFVFP
KESDTSYVSL KAPLTKPLKA FTVCLHFYTE 61 LSSTRGYSIF SYATKRQDNE
ILIFWSKDIG YSFTVGGSEI LFEVPEVTVA PVHICTSWES 121 ASGIVEFWVD
GKPRVRKSLK KGYTVGAEAS IILGQEQDSF GGNFEGSQSL VGDIGNVNMW 181
DFVLSPDEIN TIYLGGPFSP NVLNWRALKY EVQGEVFTKP QLWP
[0064] As used herein, "hepcidin" refers to a polypeptide having at
least about 85% or greater amino acid identity to the amino acid
sequence provided at NCBI Accession No. NP_066998 ("hepcidin
preprotein"), or biologically active fragment thereof. Exemplary
hepcidin biological activities include binding and reducing the
levels of the iron export channel ferroportin, inhibiting iron
transport, inhibiting intestinal iron absorption, and inhibiting
iron release from macrophages and the liver. An exemplary hepcidin
preprotein amino acid sequence is provided below:
TABLE-US-00006 (SEQ ID NO: 6) 1 MALSSQIWAA CLLLLLLLAS LTSGSVFPQQ
TGQLAELQPQ DRAGARASWM PMFQRRRRRD 61 THFPICIFCC GCCHRSKCGM CCKT
[0065] With reference to the sequence above, hepcidin exists in
various forms, including as a preprohormone (amino acids 25-84),
prohormone (amino acids 25-84), and mature forms termed hepcidin-25
(amino acids 60-84), hepcidin-22 (amino acids 63-84), and
hepcidin-20 (amino acids 65-84).
[0066] A "hepcidin-mediated disorder" is any disorder in which
hepcidin expression contributes to the etiology of the disorder or
any of its symptoms.
[0067] The term "immune suppression" or "immunosuppression" refers
to a reduction of the activation or efficacy of the immune system.
Immune suppression can be measured by the number of white blood
cells, such as neutrophils.
[0068] As used herein, "neutrophil" of "neutrocyte" refers to a
type of white blood cell that is an essential part of the innate
immune system. The absolute neutrophil count (ANC) can be used in
diagnosis and prognosis. Low neutrophil counts are termed
neutropenia.
[0069] The term "agent" refers to any compound or composition
suitable to be administered in therapy, and explicitly includes
chemical compounds; proteins, including antibodies or
antigen-binding fragments thereof; peptides; and nucleic acid
molecules.
[0070] The term "subject" refers to a human or non-human mammal,
including, but not limited to, bovine, equine, canine, ovine,
feline, and rodent, including murine and rattus, subjects. A
"patient" is a human subject in need of treatment.
[0071] As used herein, the terms "treat," "treating," "treatment,"
and the like refer to reducing or ameliorating a disorder, and/or
signs or symptoms associated therewith, or slowing or halting the
progression thereof. It will be appreciated that, although not
precluded, treating a disorder or condition does not require that
the disorder, condition or symptoms associated therewith be
completely eliminated.
[0072] As used herein, "pre-treatment" means prior to the first
administration of an IL-6 antagonist according the methods
described herein. Pre-treatment does not exclude, and often
includes, the prior administration of treatments other than an IL-6
antagonist.
[0073] As used herein, "post-treatment" means after the
administration of an IL-6 antagonist according the methods
described herein. Post-treatment includes after any administration
of an IL-6 antagonist at any dosage described herein.
Post-treatment also includes after the treatment phase of an IL-6
antagonist.
[0074] In this disclosure, "comprises," "comprising," "containing,"
"having," "includes," "including," and linguistic variants thereof
have the meaning ascribed to them in U.S. Patent law, permitting
the presence of additional components beyond those explicitly
recited.
[0075] The term "biological sample" refers to any tissue, cell,
fluid, or other material derived from an organism (e.g., human
subject). In certain embodiments, the biological sample is serum or
blood.
[0076] Unless otherwise specified, antibody constant region residue
numbering is according to the EU index as in Kabat.
2. Methods of Treating IL-6 Mediated Inflammation
[0077] In a first aspect, methods of treating IL-6-mediated
inflammation in a patient are presented. The methods comprise
administering an IL-6 antagonist to a patient with IL-6-mediated
inflammation at a dose that is sufficient to reduce inflammation
without causing immune suppression.
[0078] 2.1. Pre-Treatment Serum CRP and IL-6 Levels
[0079] In the methods described herein, the patient has an
IL-6-mediated inflammation.
[0080] In typical embodiments, the patient has elevated
pre-treatment levels of C-reactive protein (CRP).
[0081] In some embodiments, the patient has a pre-treatment CRP
level at least 2 mg/L. In some embodiments, the patient has a
pre-treatment CRP level at least 2 mg/L, 2.5 mg/L, 3 mg/L, 3.5
mg/L, 4 mg/L, 4.5 mg/L, or 5 mg/L. In some embodiments, the patient
has pre-treatment CRP levels at least 7.5 mg/L, 10 mg/L, 12.5 mg/L,
or 15 mg/L. In various embodiments, the patient has a pre-treatment
CRP level at least 2 mg/L. In various embodiments, the patient has
a pre-treatment CRP level at least 2.5 mg/L. In various
embodiments, the patient has a pre-treatment CRP level at least 5
mg/L. In various embodiments, the patient has a pre-treatment CRP
level at least 7.5 mg/L. In various embodiments, the patient has a
pre-treatment CRP level at least 10 mg/L. In various embodiments,
the patient has a pre-treatment CRP level at least 12.5 mg/L. In
various embodiments, the patient has a pre-treatment CRP level at
least 15 mg/L.
[0082] In some embodiments of the methods described herein, the
patient has elevated pre-treatment serum levels of IL-6.
[0083] In some embodiments, the patient has a pre-treatment serum
IL-6 level of at least 2 pg/ml. In various embodiments, the patient
has a pre-treatment serum IL-6 level of at least 2 pg/ml, at least
3 pg/ml, at least 4 pg/ml, at least 5 pg/ml, at least 6 pg/ml, at
least 7 pg/ml, at least 8 pg/ml, at least 9 pg/ml, at least 10
pg/ml, at least 11 pg/ml, at least 12 pg/ml, at least 13 pg/ml, at
least 14 pg/ml, or at least 15 pg/ml. In certain embodiments, the
patient has a pre-treatment serum IL-6 level of at least 2 pg/ml.
In certain embodiments, the patient has a pre-treatment serum IL-6
level of at least 2.5 pg/ml. In certain embodiments, the patient
has a pre-treatment serum IL-6 level of at least 4 pg/ml. In
certain embodiments, the patient has a pre-treatment serum IL-6
level of at least 5 pg/ml. In certain embodiments, the patient has
a pre-treatment serum IL-6 level of at least 7.5 pg/ml. In certain
embodiments, the patient has a pre-treatment serum IL-6 level of at
least 10 pg/ml. In certain embodiments, the patient has a
pre-treatment serum IL-6 level of at least 12.5 pg/ml. In certain
embodiments, the patient has a pre-treatment serum IL-6 level of at
least 15 pg/ml.
[0084] In some embodiments, the patient has elevated pre-treatment
serum levels of CRP and elevated pre-treatment IL-6 levels. In
certain embodiments, the patient has a pre-treatment serum IL-6
level of at least 2 pg/ml and a pre-treatment CRP level at least 2
mg/L. In certain embodiments, the patient has a pre-treatment serum
IL-6 level of at least 2 pg/ml and a pre-treatment CRP level at
least 2.5 mg/L. In certain embodiments, the patient has a
pre-treatment serum IL-6 level of at least 2 pg/ml and a
pre-treatment CRP level at least 5 mg/L. In certain embodiments,
the patient has a pre-treatment serum IL-6 level of at least 2
pg/ml and a pre-treatment CRP level at least 10 mg/L. In certain
embodiments, the patient has a pre-treatment serum IL-6 level of at
least 4 pg/ml and a pre-treatment CRP level at least 2 mg/L. In
certain embodiments, the patient has a pre-treatment serum IL-6
level of at least 4 pg/ml and a pre-treatment CRP level at least
2.5 mg/L. In certain embodiments, the patient has a pre-treatment
serum IL-6 level of at least 4 pg/ml and a pre-treatment CRP level
at least 5 mg/L. In certain embodiments, the patient has a
pre-treatment serum IL-6 level of at least 4 pg/ml and a
pre-treatment CRP level at least 10 mg/L. In certain embodiments,
the patient has a pre-treatment serum IL-6 level of at least 5
pg/ml and a pre-treatment CRP level at least 2 mg/L. In certain
embodiments, the patient has a pre-treatment serum IL-6 level of at
least 5 pg/ml and a pre-treatment CRP level at least 2.5 mg/L. In
certain embodiments, the patient has a pre-treatment serum IL-6
level of at least 5 pg/ml and a pre-treatment CRP level at least 5
mg/L. In certain embodiments, the patient has a pre-treatment serum
IL-6 level of at least 5 pg/ml and a pre-treatment CRP level at
least 10 mg/L. In certain embodiments, the patient has a
pre-treatment serum IL-6 level of at least 10 pg/ml and a
pre-treatment CRP level at least 2 mg/L. In certain embodiments,
the patient has a pre-treatment serum IL-6 level of at least 10
pg/ml and a pre-treatment CRP level at least 2.5 mg/L. In certain
embodiments, the patient has a pre-treatment serum IL-6 level of at
least 10 pg/ml and a pre-treatment CRP level at least 5 mg/L. In
certain embodiments, the patient has a pre-treatment serum IL-6
level of at least 10 pg/ml and a pre-treatment CRP level at least
10 mg/L.
[0085] 2.2. Reduction of IL-6 and C-Reactive Protein (CRP)
[0086] In typical embodiments, the IL-6 antagonist is administered
at a dose sufficient to reduce the patient's free serum IL-6 levels
below pre-treatment levels.
[0087] In some embodiments, the free serum IL-6 level is decreased
by at least 10% as compared to pre-treatment levels. In various
embodiments, the free serum IL-6 level is decreased by at least
20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to
pre-treatment levels. In certain embodiments, the free serum IL-6
level is decreased by at least 20% as compared to pre-treatment
levels. In certain embodiments, the free serum IL-6 level is
decreased by at least 30% as compared to pre-treatment levels. In
certain embodiments, the free serum IL-6 level is decreased by at
least 40% as compared to pre-treatment levels. In certain
embodiments, the free serum IL-6 level is decreased by at least 50%
as compared to pre-treatment levels. In certain embodiments, the
free serum IL-6 level is decreased by at least 60% as compared to
pre-treatment levels. In certain embodiments, the free serum IL-6
level is decreased by at least 70% as compared to pre-treatment
levels. In certain embodiments, the free serum IL-6 level is
decreased by at least 80% as compared to pre-treatment levels. In
certain embodiments, the free serum IL-6 level is decreased by at
least 90% as compared to pre-treatment levels.
[0088] In some embodiments, the IL-6 antagonist is administered at
a dose sufficient to reduce the patient's CRP levels below
pre-treatment levels. In some embodiments, the IL-6 mediated
inflammation is measured by the CRP levels.
[0089] In certain embodiments, the post-treatment CRP level is no
more than 5 mg/L. In certain embodiments, the post-treatment CRP
level is no more than 2.5 mg/L. In certain embodiments, the
post-treatment CRP level is no more than 2 mg/L. In certain
embodiments, the post-treatment CRP level is no more than 1
mg/L.
[0090] In some embodiments, the CRP level is decreased by at least
10% as compared to pre-treatment levels. In various embodiments,
the CRP level is decreased by at least 20%, 30%, 40%, 50%, 60%,
70%, 80%, or 90% as compared to pre-treatment levels. In certain
embodiments, the CRP level is decreased by at least 20% as compared
to pre-treatment levels. In certain embodiments, the CRP level is
decreased by at least 30% as compared to pre-treatment levels. In
certain embodiments, the CRP level is decreased by at least 40% as
compared to pre-treatment levels. In certain embodiments, the CRP
level is decreased by at least 50% as compared to pre-treatment
levels. In certain embodiments, the CRP level is decreased by at
least 60% as compared to pre-treatment levels. In certain
embodiments, the CRP level is decreased by at least 70% as compared
to pre-treatment levels. In certain embodiments, the CRP level is
decreased by at least 80% as compared to pre-treatment levels. In
certain embodiments, the CRP level is decreased by at least 90% as
compared to pre-treatment levels.
[0091] 2.3. Neutrophil Level
[0092] 2.3.1. Absolute Neutrophil Count (ANC)
[0093] In the methods described herein, the IL-6 antagonist is
administered at a dose sufficient to reduce inflammation without
causing immune suppression.
[0094] In some embodiments, the immune suppression of the patient
is measured by Absolute Neutrophil Count (ANC).
[0095] In some embodiments, the post-treatment ANC is at least 300
cells/.mu.L. In various embodiments, the post-treatment ANC is at
least 500 cells/.mu.L, 600 cells/.mu.L, 700 cells/.mu.L, 800
cells/.mu.L, 900 cells/.mu.L, 1000 cells/.mu.L, 1100 cells/.mu.L,
1200 cells/.mu.L, 1300 cells/.mu.L, 1400 cells/.mu.L, 1500
cells/.mu.L, 1600 cells/.mu.L, 1700 cells/.mu.L, 1800 cells/.mu.L,
1900 cells/.mu.L, or 2000 cells/.mu.L. In certain embodiments, the
post-treatment ANC is at least 500 cells/.mu.L. In certain
embodiments, the post-treatment ANC is at least 750 cells/.mu.L. In
certain embodiments, the post-treatment ANC is at least 1000
cells/.mu.L. In certain embodiments, the post-treatment ANC is at
least 1250 cells/.mu.L. In certain embodiments, the post-treatment
ANC is at least 1500 cells/.mu.L. In certain embodiments, the
post-treatment ANC is at least 1750 cells/.mu.L. In certain
embodiments, the post-treatment ANC is at least 2000
cells/.mu.L.
[0096] In some embodiments, the ANC is decreased by no more than
2500 cells/.mu.L as compared to pre-treatment levels. In various
embodiments, the ANC is decreased by no more than 2000 cells/.mu.L,
1900 cells/.mu.L, 1800 cells/.mu.L, 1700 cells/.mu.L, 1600
cells/.mu.L, 1500 cells/.mu.L, 1400 cells/.mu.L, 1300 cells/.mu.L,
1200 cells/.mu.L, 1100 cells/.mu.L, 1000 cells/.mu.L, 900
cells/.mu.L, 800 cells/.mu.L, 700 cells/.mu.L, 600 cells/.mu.L, or
500 cells/.mu.L, as compared to pre-treatment levels. In certain
embodiments, the ANC is decreased by no more than 2000 cells/.mu.L
as compared to pre-treatment levels. In certain embodiments, the
ANC is decreased by no more than 1750 cells/.mu.L as compared to
pre-treatment levels. In certain embodiments, the ANC is decreased
by no more than 1500 cells/.mu.L as compared to pre-treatment
levels. In certain embodiments, the ANC is decreased by no more
than 1250 cells/.mu.L as compared to pre-treatment levels. In
certain embodiments, the ANC is decreased by no more than 1000
cells/.mu.L as compared to pre-treatment levels. In certain
embodiments, the ANC is decreased by no more than 750 cells/.mu.L
as compared to pre-treatment levels. In certain embodiments, the
ANC is decreased by no more than 500 cells/.mu.L as compared to
pre-treatment levels.
[0097] In some embodiments, the ANC is decreased by no more than
70% as compared to pre-treatment levels. In various embodiments,
the ANC is decreased by no more than 60%, 50%, 40%, 30%, 20%, 10%,
or 5% as compared to pre-treatment levels. In certain embodiments,
the ANC is decreased by no more than 60% as compared to
pre-treatment levels. In certain embodiments, the ANC is decreased
by no more than 50% as compared to pre-treatment levels. In certain
embodiments, the ANC is decreased by no more than 40% as compared
to pre-treatment levels. In certain embodiments, the ANC is
decreased by no more than 30% as compared to pre-treatment levels.
In certain embodiments, the ANC is decreased by no more than 20% as
compared to pre-treatment levels. In certain embodiments, the ANC
is decreased by no more than 10% as compared to pre-treatment
levels. In certain embodiments, the ANC is decreased by no more
than 5% as compared to pre-treatment levels.
[0098] In some embodiments, the ANC is not decreased as compared to
pre-treatment levels.
[0099] 2.4. Lipoprotein(a) Level
[0100] In some embodiments, the IL-6 antagonist is administered at
a dose sufficient to reduce the patient's lipoprotein(a) levels
below pre-treatment levels.
[0101] In some embodiments, the lipoprotein(a) level is decreased
by at least 10% as compared to pre-treatment levels. In various
embodiments, the lipoprotein(a) level is decreased by at least 20%,
30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment
levels. In certain embodiments, the lipoprotein(a) level is
decreased by at least 20% as compared to pre-treatment levels. In
certain embodiments, the lipoprotein(a) level is decreased by at
least 30% as compared to pre-treatment levels. In certain
embodiments, the lipoprotein(a) level is decreased by at least 40%
as compared to pre-treatment levels. In certain embodiments, the
lipoprotein(a) level is decreased by at least 50% as compared to
pre-treatment levels. In certain embodiments, the lipoprotein(a)
level is decreased by at least 60% as compared to pre-treatment
levels. In certain embodiments, the lipoprotein(a) level is
decreased by at least 70% as compared to pre-treatment levels. In
certain embodiments, the lipoprotein(a) level is decreased by at
least 80% as compared to pre-treatment levels. In certain
embodiments, the lipoprotein(a) level is decreased by at least 90%
as compared to pre-treatment levels.
[0102] 2.5. LDL Level
[0103] In some embodiments, the IL-6 antagonist is administered at
a dose sufficient to reduce the patient's lipoprotein(a) levels
without significantly increasing the patent's low-density
lipoprotein (LDL) levels.
[0104] In some embodiments, the LDL level is increased by no more
than 15% as compared to pre-treatment levels. In various
embodiments, the LDL level is increased by no more than 12%, 10%,
8%, 6%, 5%, 4%, 3%, 2% or 1% as compared to pre-treatment levels.
In certain embodiments, the LDL level is increased by no more than
12% as compared to pre-treatment levels. In certain embodiments,
the LDL level is increased by no more than 10% as compared to
pre-treatment levels. In certain embodiments, the LDL level is
increased by no more than 8% as compared to pre-treatment levels.
In certain embodiments, the LDL level is increased by no more than
6% as compared to pre-treatment levels. In certain embodiments, the
LDL level is increased by no more than 5% as compared to
pre-treatment levels. In certain embodiments, the LDL level is
increased by no more than 4% as compared to pre-treatment levels.
In certain embodiments, the LDL level is increased by no more than
3% as compared to pre-treatment levels. In certain embodiments, the
LDL level is increased by no more than 2% as compared to
pre-treatment levels. In certain embodiments, the LDL level is
increased by no more than 1% as compared to pre-treatment
levels.
[0105] In certain embodiments, the LDL level is not increased as
compared to pre-treatment levels.
[0106] 2.6. IL-6 Mediated Inflammatory Disorders
[0107] In the methods described herein, the patient has an IL-6
mediated inflammatory disorder.
[0108] 2.6.1. Non-hepcidin-mediated inflammatory disorders
[0109] In various embodiments, the IL-6 mediated inflammatory
disorder is not a hepcidin-mediated disorder. Hepcidin-mediated
disorders are described in US 2017/0029499, the disclosure of which
is incorporated herein by reference in its entirety.
[0110] 2.6.2. Hepcidin-mediated inflammatory disorders
[0111] In various embodiments, the IL-6 mediated inflammatory
disorder is a hepcidin-mediated disorder. Hepcidin-mediated
disorders are described in US 2017/0029499, the disclosure of which
is incorporated herein by reference in its entirety. In particular
embodiments, the patient has a hepcidin-mediated disorder and at
least one copy of the major allele at the TMPRSS6 rs855791 SNP
(amino acid 736A). In other embodiments, the patient has a
hepcidin-mediated disorder and is homozygous for the minor allele
at the TMPRSS6 rs855791 SNP (amino acid 736V). In certain
embodiments, the patient has a hepcidin-mediated disorder and
unknown genotype at the TMPRSS6 rs855791 SNP.
[0112] 2.6.3. Non-Autoimmune Inflammatory Disorder
[0113] In various embodiments, the IL-6 mediated inflammatory
disorder is a non-autoimmune IL-6 mediated inflammatory disorder.
In particular embodiments, the patient has an IL-6 mediated
disorder other than rheumatoid arthritis, giant cell arteritis,
polyarticular juvenile idiopathic arthritis, or systemic juvenile
idiopathic arthritis.
[0114] 2.6.4. Kidney Disease
[0115] In various embodiments, the patient has kidney disease. In
some embodiments, the kidney disease is chronic kidney disease
(CKD).
[0116] In some embodiments, the patient has KDOQI stage 1-5 chronic
kidney disease. In some embodiments, the patient has KDOQI stage
3-5 chronic kidney disease. In some embodiments, the patient has
KDOQI stage 1 chronic kidney disease, KDOQI stage 2 chronic kidney
disease, KDOQI stage 3 chronic kidney disease, KDOQI stage 4
chronic kidney disease, or KDOQI stage 5 chronic kidney disease. In
certain embodiments, the patient has KDOQI stage 5 chronic kidney
disease.
[0117] In some embodiments, the patient is on dialysis. In some
embodiments, the patient is not on dialysis. In certain embodiment,
the patient has KDOQI stage 3-5 chronic kidney disease, wherein the
patient is not on dialysis. In certain embodiment, the patient has
KDOQI stage 5 chronic kidney disease, wherein the patient is on
dialysis.
[0118] In some embodiments, the patient has cardiorenal syndrome
(CRS). In certain embodiments, the patient has CRS Type 4.
[0119] In some embodiments, the patient has been treated with
dialysis.
[0120] 2.6.5. Cardiovascular Disease
[0121] In various embodiments, the patient has cardiovascular
disease.
[0122] In some embodiments, the patient has had a previous
myocardial infarction. In particular embodiments, the patient has
had a previous myocardial infarction and has a CRP level of 2 mg/L
or more.
[0123] In certain embodiments, the patient has suffered a
myocardial infarction within the 60 days prior to first
administration of an IL-6 antagonist. In particular embodiments,
the patient has suffered a myocardial infarction within the 30
days, 14 days, 7 days, 48 hours, or 24 hours prior to first
administration of an IL-6 antagonist.
[0124] In some embodiments, the patient has atherosclerosis but has
not had a myocardial infarction. In particular embodiments, the
patient has atherosclerosis, has not had a myocardial infarction,
and has a CRP level of 2 mg/L or more.
[0125] In some embodiments, the cardiovascular disease is
congestive heart failure (CHF). In certain embodiments, the patient
has congestive heart failure (CHF) with reduced ejection fraction.
In certain embodiments, the patient has congestive heart failure
(CHF) with mid-range ejection fraction. In certain embodiments, the
patient has congestive heart failure (CHF) with preserved ejection
fraction.
[0126] In various embodiments, the IL-6 mediated inflammatory
disorder is heart failure that is not diuretic resistant. Diuretic
resistant heart failure is described in WO 2018/144773, the
disclosure of which is incorporated herein by reference in its
entirety.
[0127] In some embodiments, the cardiovascular disease is diuretic
resistant heart failure. Diuretic resistant heart failure is
described in WO 2018/144773, the disclosure of which is
incorporated herein by reference in its entirety.
[0128] In some embodiments, the cardiovascular disease is acute
coronary syndrome.
[0129] In certain embodiments, the IL-6 antagonist is administered
at a dose sufficient to reduce nonfatal myocardial infarction,
nonfatal stroke, and/or cardiovascular death. In some embodiments,
the IL-6 antagonist is administered at a dose sufficient to reduce
the risk of heart failure. In some embodiments, the IL-6 antagonist
is administered at a dose sufficient to increase cardiac function.
In some embodiments, the IL-6 antagonist is administered at a dose
sufficient to reduce fibrosis after acute myocardial
infarction.
[0130] 2.6.6. Anemia
[0131] In various embodiments, the patient has anemia.
[0132] In some embodiments, the patient has anemia of chronic
disease. In some embodiments, the patient has iron-refractory
iron-deficiency anemia (IRIDA).
[0133] In some of these embodiments, the patient has been treated
with an erythropoiesis-stimulating agent (ESA). In some
embodiments, the patient has been treated with iron
supplementation. In some embodiments, the patient has been treated
with transfusion of blood or packed red blood cells.
[0134] In some embodiments, the IL-6 antagonist is administered at
a dose sufficient to reverse functional iron deficiency.
[0135] 2.6.7. Diabetes
[0136] In some embodiments, the patient has diabetes. In certain
embodiments, the patient has type II diabetes. In certain
embodiments, the patient has insulin-resistant diabetes.
[0137] 2.6.8. Liver Disease
[0138] In some embodiments, the patient has liver disease. In
certain embodiments, the patient has non-alcoholic steatohepatitis
(NASH).
[0139] 2.6.9. Osteoporosis
[0140] In some embodiments, the patient has osteoporosis.
[0141] 2.6.10. Depression
[0142] In some embodiments, the patient has depression.
[0143] 2.6.11. Asthma
[0144] In some embodiments, the patient has asthma.
[0145] 2.6.12. Neuroinflammatory Disorder
[0146] In some embodiments, the patient has neuroinflammatory
disorder. In certain embodiments, the patient has Alzheimer's
disease. In certain embodiments, the patient has Parkinson's
disease. In certain embodiments, the patient has multiple
sclerosis. In certain embodiments, the patient has amyotrophic
lateral sclerosis (ALS).
[0147] 2.6.13. Age-Related Macular Degeneration
[0148] In some embodiments, the patient has age-related macular
degeneration (AMD).
[0149] 2.6.14. Cancer
[0150] In various embodiments, the patient has cancer.
[0151] In some embodiments, the cancer is selected from the group
consisting of: solid tumors, small cell lung cancer, non-small cell
lung cancer, hematological cancer, multiple myeloma, leukemia,
chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML),
lymphomas, and Hodgkin's lymphoma.
[0152] 2.6.15. Skin Disease
[0153] In various embodiments, the patient has skin disease, such
as atopic dermatitis or psoriasis.
[0154] 2.6.16. Aging
[0155] In some embodiments, the method prevents aging in the
patient.
[0156] 2.7. IL-6 Antagonists
[0157] The IL-6 antagonist used in the methods described herein is
capable of decreasing the biological activity of IL-6.
[0158] 2.7.1. Anti-IL-6 Antibodies
[0159] In various embodiments, the IL-6 antagonist is an anti-IL-6
antibody or antigen-binding fragment or derivative thereof.
[0160] In typical embodiments, the anti-IL-6 antibody neutralizes
the biological activity of IL-6. In some embodiments, the
neutralizing antibody prevents binding of IL-6 to the IL-6
receptor.
[0161] In some embodiments, the IL-6 antagonist is an anti-IL-6
monoclonal antibody. In some embodiments, the IL-6 antagonist is a
polyclonal composition comprising a plurality of species of
anti-IL-6 antibodies, each of the plurality having unique CDRs.
[0162] In some embodiments, the anti-IL-6 antibody is a Fab, Fab',
F(ab').sub.2, Fv, scFv, (scFv).sub.2, single chain antibody
molecule, dual variable domain antibody, single variable domain
antibody, linear antibody, or V domain antibody.
[0163] In some embodiments, the anti-IL-6 antibody comprises a
scaffold. In certain embodiments, the scaffold is Fc, optionally
human Fc. In some embodiments, the anti-IL-6 antibody comprises a
heavy chain constant region of a class selected from IgG, IgA, IgD,
IgE, and IgM. In certain embodiments, the anti-IL-6 antibody
comprises a heavy chain constant region of the class IgG and a
subclass selected from IgG1, IgG2, IgG3, and IgG4.
[0164] In some embodiments, the IL-6 antagonist is immunoconjugate
or fusion protein comprising an IL-6 antigen-binding fragment.
[0165] In some embodiments, the antibody is bispecific or
multispecific, with at least one of the antigen-binding portions
having specificity for IL-6.
[0166] In some embodiments, the antibody is fully human. In some
embodiments, the antibody is humanized. In some embodiments, the
antibody is chimeric and has non-human V regions and human C region
domains. In some embodiments, the antibody is murine.
[0167] In typical embodiments, the anti-IL-6 antibody has a K.sub.D
for binding human IL-6 of less than 100 nM. In some embodiments,
the anti-IL-6 antibody has a K.sub.D for binding human IL-6 of less
than 75 nM, 50 nM, 25 nM, 20 nM, 15 nM, or 10 nM. In particular
embodiments, the anti-IL-6 antibody has a K.sub.D for binding human
IL-6 of less than 5 nM, 4 nM, 3 nM, or 2 nM. In selected
embodiments, the anti-IL-6 antibody has a K.sub.D for binding human
IL-6 of less than 1 nM, 750 pM, or 500 pM. In specific embodiments,
the anti-IL-6 antibody has a K.sub.D for binding human IL-6 of no
more than 500 pM, 400 pM, 300 pM, 200 pM, or 100 pM.
[0168] In typical embodiments, the anti-IL-6 antibody has an
elimination half-life following intravenous administration of at
least 7 days. In certain embodiments, the anti-IL-6 antibody has an
elimination half-life of at least 14 days, at least 21 days, or at
least 30 days.
[0169] In some embodiments, the anti-IL-6 antibody has a human IgG
constant region with at least one amino acid substitution that
extends serum half-life as compared to the unsubstituted human IgG
constant domain.
[0170] In certain embodiments, the IgG constant domain comprises
substitutions at residues 252, 254, and 256, wherein the amino acid
substitution at amino acid residue 252 is a substitution with
tyrosine, the amino acid substitution at amino acid residue 254 is
a substitution with threonine, and the amino acid substitution at
amino acid residue 256 is a substitution with glutamic acid
("YTE"). See U.S. Pat. No. 7,083,784, incorporated herein by
reference in its entirety. In certain extended half-life
embodiments, the IgG constant domain comprises substitutions
selected from T250Q/M428L (Hinton et al., J. Immunology 176:346-356
(2006)); N434A (Yeung et al., J. Immunology 182:7663-7671 (2009));
or T307A/E380A/N434A (Petkova et al., International Immunology, 18:
1759-1769 (2006)).
[0171] In some embodiments, the elimination half-life of the
anti-IL-6 antibody is increased by utilizing the FcRN-binding
properties of human serum albumin. In certain embodiments, the
antibody is conjugated to albumin (Smith et al., Bioconjug. Chem.,
12: 750-756 (2001)). In some embodiments, the anti-IL-6 antibody is
fused to bacterial albumin-binding domains (Stork et al., Prot.
Eng. Design Science 20: 569-76 (2007)). In some embodiments, the
anti-IL-6 antibody is fused to an albumin-binding peptide (Nguygen
et al., Prot Eng Design Sel 19: 291-297 (2006)). In some
embodiments, the anti-IL-6 antibody is bispecific, with one
specificity being to IL-6, and one specificity being to human serum
albumin (Ablynx, WO 2006/122825 (bispecific Nanobody)).
[0172] In some embodiments, the elimination half-life of the
anti-IL-6 antibody is increased by PEGylation (Melmed et al.,
Nature Reviews Drug Discovery 7: 641-642 (2008)); by HPMA copolymer
conjugation (Lu et al., Nature Biotechnology 17: 1101-1104 (1999));
by dextran conjugation (Nuclear Medicine Communications, 16:
362-369 (1995)); by conjugation with homo-amino-acid polymers
(HAPs; HAPylation) (Schlapschy et al., Prot Eng Design Sel 20:
273-284 (2007)); or by polysialylation (Constantinou et al.,
Bioconjug. Chem. 20: 924-931 (2009)).
[0173] 2.7.1.1. COR-001 and Derivatives
[0174] In certain preferred embodiments, the anti-IL-6 antibody or
antigen-binding portion thereof comprises all six CDRs of COR-001.
The COR-001 antibody (also known as MEDI5117) is described in WO
2010/088444 and US 2012/0034212, the disclosures of which are
incorporated herein by reference in their entireties. In particular
embodiments, the antibody or antigen-binding portion thereof
comprises the COR-001 heavy chain V region and light chain V
region. In specific embodiments, the antibody is the full-length
COR-001 antibody. The COR-001 antibody has the following CDR and
heavy and light chain sequences:
TABLE-US-00007 COR-001 VH CDR1 (SEQ ID NO: 7) SNYMI COR-001 VH CDR2
(SEQ ID NO: 8) DLYYYAGDTYYADSVKG COR-001 VH CDR3 (SEQ ID NO: 9)
WADDHPPWIDL COR-001 VL CDR1 (SEQ ID NO: 10) RASQGISSWLA COR-001 VL
CDR2 (SEQ ID NO: 11) KASTLES COR-001 VL CDR3 (SEQ ID NO: 12)
QQSWLGGS COR-001 Heavy chain (SEQ ID NO: 13)
EVQLVESGGGLVQPGGSLRLSCAASGFTISSNYMIWVRQAPGKGLEWVSD
LYYYAGDTYYADSVKGRFTMSRDISKNTVYLQMNSLRAEDTAVYYCARWA
DDHPPWIDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK
DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT
YICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP
KDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK COR-001 Light
chain (SEQ ID NO: 14)
DIQMTQSPSTLSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKVLIYK
ASTLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQSWLGGSFGQG
TKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD
NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL
SSPVTKSFNRGEC
[0175] In various embodiments, the anti-IL-6 antibody is a
derivative of COR-001.
[0176] In some embodiments, the COR-001 derivative includes one or
more amino acid substitutions in the COR-001 heavy and/or light
chain V regions.
[0177] In certain embodiments, the COR-001 derivative comprises
fewer than 25 amino acid substitutions, fewer than 20 amino acid
substitutions, fewer than 15 amino acid substitutions, fewer than
10 amino acid substitutions, fewer than 5 amino acid substitutions,
fewer than 4 amino acid substitutions, fewer than 3 amino acid
substitutions, fewer than 2 amino acid substitutions, or 1 amino
acid substitution relative to the original V.sub.H and/or V.sub.L
of the COR-001 anti-IL-6 antibody, while retaining specificity for
human IL-6.
[0178] In certain embodiments, the COR-001 derivative comprises an
amino acid sequence that is at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, at least 90%, at least 95%, or at least
99% identical to the amino acid sequence of the V.sub.H and V.sub.L
domain of COR-001. The percent sequence identity is determined
using BLAST algorithms using default parameters.
[0179] In certain embodiments, the COR-001 derivative comprises an
amino acid sequence in which the CDRs comprise an amino acid
sequence that is at least 45%, at least 50%, at least 55%, at least
60%, at least 65%, at least 70%, at least 75%, at least 80%, at
least 85%, at least 90%, at least 95%, or at least 99% identical to
the amino acid sequence of the respective CDRs of COR-001. The
percent sequence identity is determined using BLAST algorithms
using default parameters.
[0180] In certain embodiments, the V.sub.H and/or V.sub.L CDR
derivatives comprise conservative amino acid substitutions at one
or more predicted nonessential amino acid residues (i.e., amino
acid residues which are not critical for the antibody to
specifically bind to human IL-6).
[0181] 2.7.1.2. Siltuximab and Derivatives
[0182] In certain embodiments, the anti-IL-6 antibody or
antigen-binding portion thereof comprises all six CDRs of
siltuximab. In particular embodiments, the antibody or
antigen-binding portion thereof comprises the siltuximab heavy
chain V region and light chain V region. In specific embodiments,
the antibody is the full-length siltuximab antibody.
[0183] In various embodiments, the anti-IL-6 antibody is a
derivative of siltuximab.
[0184] In some embodiments, the siltuximab derivative includes one
or more amino acid substitutions in the siltuximab heavy and/or
light chain V regions.
[0185] In certain embodiments, the siltuximab derivative comprises
fewer than 25 amino acid substitutions, fewer than 20 amino acid
substitutions, fewer than 15 amino acid substitutions, fewer than
10 amino acid substitutions, fewer than 5 amino acid substitutions,
fewer than 4 amino acid substitutions, fewer than 3 amino acid
substitutions, fewer than 2 amino acid substitutions, or 1 amino
acid substitution relative to the original V.sub.H and/or V.sub.L
of the siltuximab anti-IL-6 antibody, while retaining specificity
for human IL-6.
[0186] In certain embodiments, the siltuximab derivative comprises
an amino acid sequence that is at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, at least 90%, at least 95%, or at least
99% identical to the amino acid sequence of the V.sub.H and V.sub.L
domain of siltuximab. The percent sequence identity is determined
using BLAST algorithms using default parameters.
[0187] In certain embodiments, the siltuximab derivative comprises
an amino acid sequence in which the CDRs comprise an amino acid
sequence that is at least 45%, at least 50%, at least 55%, at least
60%, at least 65%, at least 70%, at least 75%, at least 80%, at
least 85%, at least 90%, at least 95%, or at least 99% identical to
the amino acid sequence of the respective CDRs of siltuximab. The
percent sequence identity is determined using BLAST algorithms
using default parameters.
[0188] In certain embodiments, the V.sub.H and/or V.sub.L CDR
derivatives comprise conservative amino acid substitutions at one
or more predicted nonessential amino acid residues (i.e., amino
acid residues which are not critical for the antibody to
specifically bind to human IL-6).
[0189] 2.7.1.3. Gerilimzumab and Derivatives
[0190] In certain embodiments, the anti-IL-6 antibody or
antigen-binding portion thereof comprises all six CDRs of
gerilimzumab. In particular embodiments, the antibody or
antigen-binding portion thereof comprises the gerilimzumab heavy
chain V region and light chain V region. In specific embodiments,
the antibody is the full-length gerilimzumab antibody.
[0191] In various embodiments, the anti-IL-6 antibody is a
derivative of gerilimzumab.
[0192] In some embodiments, the gerilimzumab derivative includes
one or more amino acid substitutions in the gerilimzumab heavy
and/or light chain V regions.
[0193] In certain embodiments, the gerilimzumab derivative
comprises fewer than 25 amino acid substitutions, fewer than 20
amino acid substitutions, fewer than 15 amino acid substitutions,
fewer than 10 amino acid substitutions, fewer than 5 amino acid
substitutions, fewer than 4 amino acid substitutions, fewer than 3
amino acid substitutions, fewer than 2 amino acid substitutions, or
1 amino acid substitution relative to the original V.sub.H and/or
V.sub.L of the gerilimzumab anti-IL-6 antibody, while retaining
specificity for human IL-6.
[0194] In certain embodiments, the gerilimzumab derivative
comprises an amino acid sequence that is at least 45%, at least
50%, at least 55%, at least 60%, at least 65%, at least 70%, at
least 75%, at least 80%, at least 85%, at least 90%, at least 95%,
or at least 99% identical to the amino acid sequence of the V.sub.H
and V.sub.L domain of gerilimzumab. The percent sequence identity
is determined using BLAST algorithms using default parameters.
[0195] In certain embodiments, the gerilimzumab derivative
comprises an amino acid sequence in which the CDRs comprise an
amino acid sequence that is at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, at least 90%, at least 95%, or at least
99% identical to the amino acid sequence of the respective CDRs of
gerilimzumab. The percent sequence identity is determined using
BLAST algorithms using default parameters.
[0196] In certain embodiments, the V.sub.H and/or V.sub.L CDR
derivatives comprise conservative amino acid substitutions at one
or more predicted nonessential amino acid residues (i.e., amino
acid residues which are not critical for the antibody to
specifically bind to human IL-6).
[0197] 2.7.1.4. Sirukumab and Derivatives
[0198] In certain embodiments, the anti-IL-6 antibody or
antigen-binding portion thereof comprises all six CDRs of
sirukumab. In particular embodiments, the antibody or
antigen-binding portion thereof comprises the sirukumab heavy chain
V region and light chain V region. In specific embodiments, the
antibody is the full-length sirukumab antibody.
[0199] In various embodiments, the anti-IL-6 antibody is a
derivative of sirukumab.
[0200] In some embodiments, the sirukumab derivative includes one
or more amino acid substitutions in the sirukumab heavy and/or
light chain V regions.
[0201] In certain embodiments, the sirukumab derivative comprises
fewer than 25 amino acid substitutions, fewer than 20 amino acid
substitutions, fewer than 15 amino acid substitutions, fewer than
10 amino acid substitutions, fewer than 5 amino acid substitutions,
fewer than 4 amino acid substitutions, fewer than 3 amino acid
substitutions, fewer than 2 amino acid substitutions, or 1 amino
acid substitution relative to the original V.sub.H and/or V.sub.L
of the sirukumab anti-IL-6 antibody, while retaining specificity
for human IL-6.
[0202] In certain embodiments, the sirukumab derivative comprises
an amino acid sequence that is at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, at least 90%, at least 95%, or at least
99% identical to the amino acid sequence of the V.sub.H and V.sub.L
domain of sirukumab. The percent sequence identity is determined
using BLAST algorithms using default parameters.
[0203] In certain embodiments, the sirukumab derivative comprises
an amino acid sequence in which the CDRs comprise an amino acid
sequence that is at least 45%, at least 50%, at least 55%, at least
60%, at least 65%, at least 70%, at least 75%, at least 80%, at
least 85%, at least 90%, at least 95%, or at least 99% identical to
the amino acid sequence of the respective CDRs of sirukumab. The
percent sequence identity is determined using BLAST algorithms
using default parameters.
[0204] In certain embodiments, the V.sub.H and/or V.sub.L CDR
derivatives comprise conservative amino acid substitutions at one
or more predicted nonessential amino acid residues (i.e., amino
acid residues which are not critical for the antibody to
specifically bind to human IL-6).
[0205] 2.7.1.5. Clazakizumab and Derivatives
[0206] In certain embodiments, the anti-IL-6 antibody or
antigen-binding portion thereof comprises all six CDRs of
clazakizumab. In particular embodiments, the antibody or
antigen-binding portion thereof comprises the clazakizumab heavy
chain V region and light chain V region. In specific embodiments,
the antibody is the full-length clazakizumab antibody.
[0207] In various embodiments, the anti-IL-6 antibody is a
derivative of clazakizumab.
[0208] In some embodiments, the clazakizumab derivative includes
one or more amino acid substitutions in the clazakizumab heavy
and/or light chain V regions.
[0209] In certain embodiments, the clazakizumab derivative
comprises fewer than 25 amino acid substitutions, fewer than 20
amino acid substitutions, fewer than 15 amino acid substitutions,
fewer than 10 amino acid substitutions, fewer than 5 amino acid
substitutions, fewer than 4 amino acid substitutions, fewer than 3
amino acid substitutions, fewer than 2 amino acid substitutions, or
1 amino acid substitution relative to the original V.sub.H and/or
V.sub.L of the clazakizumab anti-IL-6 antibody, while retaining
specificity for human IL-6.
[0210] In certain embodiments, the clazakizumab derivative
comprises an amino acid sequence that is at least 45%, at least
50%, at least 55%, at least 60%, at least 65%, at least 70%, at
least 75%, at least 80%, at least 85%, at least 90%, at least 95%,
or at least 99% identical to the amino acid sequence of the V.sub.H
and V.sub.L domain of clazakizumab. The percent sequence identity
is determined using BLAST algorithms using default parameters.
[0211] In certain embodiments, the clazakizumab derivative
comprises an amino acid sequence in which the CDRs comprise an
amino acid sequence that is at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, at least 90%, at least 95%, or at least
99% identical to the amino acid sequence of the respective CDRs of
clazakizumab. The percent sequence identity is determined using
BLAST algorithms using default parameters.
[0212] In certain embodiments, the V.sub.H and/or V.sub.L CDR
derivatives comprise conservative amino acid substitutions at one
or more predicted nonessential amino acid residues (i.e., amino
acid residues which are not critical for the antibody to
specifically bind to human IL-6).
[0213] 2.7.1.6. Olokizumab and Derivatives
[0214] In certain embodiments, the anti-IL-6 antibody or
antigen-binding portion thereof comprises all six CDRs of
olokizumab. In particular embodiments, the antibody or
antigen-binding portion thereof comprises the olokizumab heavy
chain V region and light chain V region. In specific embodiments,
the antibody is the full-length olokizumab antibody.
[0215] In various embodiments, the anti-IL-6 antibody is a
derivative of olokizumab.
[0216] In some embodiments, the olokizumab derivative includes one
or more amino acid substitutions in the olokizumab heavy and/or
light chain V regions.
[0217] In certain embodiments, the olokizumab derivative comprises
fewer than 25 amino acid substitutions, fewer than 20 amino acid
substitutions, fewer than 15 amino acid substitutions, fewer than
10 amino acid substitutions, fewer than 5 amino acid substitutions,
fewer than 4 amino acid substitutions, fewer than 3 amino acid
substitutions, fewer than 2 amino acid substitutions, or 1 amino
acid substitution relative to the original V.sub.H and/or V.sub.L
of the olokizumab anti-IL-6 antibody, while retaining specificity
for human IL-6.
[0218] In certain embodiments, the olokizumab derivative comprises
an amino acid sequence that is at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, at least 90%, at least 95%, or at least
99% identical to the amino acid sequence of the V.sub.H and V.sub.L
domain of olokizumab. The percent sequence identity is determined
using BLAST algorithms using default parameters.
[0219] In certain embodiments, the olokizumab derivative comprises
an amino acid sequence in which the CDRs comprise an amino acid
sequence that is at least 45%, at least 50%, at least 55%, at least
60%, at least 65%, at least 70%, at least 75%, at least 80%, at
least 85%, at least 90%, at least 95%, or at least 99% identical to
the amino acid sequence of the respective CDRs of olokizumab. The
percent sequence identity is determined using BLAST algorithms
using default parameters.
[0220] In certain embodiments, the V.sub.H and/or V.sub.L CDR
derivatives comprise conservative amino acid substitutions at one
or more predicted nonessential amino acid residues (i.e., amino
acid residues which are not critical for the antibody to
specifically bind to human IL-6).
[0221] 2.7.1.7. Other Anti-IL-6 Antibodies and Derivatives
[0222] In certain embodiments, the anti-IL-6 antibody or
antigen-binding portion thereof comprises all six CDRs of an
antibody selected from the group consisting of: VX30 (VOP-R003;
Vaccinex), EB-007 (EBI-029; Eleven Bio), and FM101. In particular
embodiments, the antibody or antigen-binding portion thereof
comprises the heavy chain V region and light chain V region of an
antibody selected from the group consisting of: VX30 (VOP-R003;
Vaccinex), EB-007 (EBI-029; Eleven Bio), and FM101. In specific
embodiments, the antibody is a full-length antibody selected from
the group consisting of: VX30 (VOP-R003; Vaccinex), EB-007
(EBI-029; Eleven Bio), and FM101.
[0223] In various embodiments, the anti-IL-6 antibody is a
derivative of an antibody selected from the group consisting of:
VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), and
FM101.
[0224] 2.7.2. Anti-IL-6 Receptor Antibodies
[0225] In various embodiments, the IL-6 antagonist is an anti-IL-6
receptor (anti-IL-6R) antibody or antigen-binding fragment or
derivative thereof.
[0226] In typical embodiments, the anti-IL-6R reduces the
biological activity of IL-6 receptor.
[0227] In some embodiments, the IL-6 antagonist is an anti-IL-6R
monoclonal antibody. In some embodiments, the IL-6 antagonist is a
polyclonal composition comprising a plurality of species of
anti-IL-6R antibodies, each of the plurality having unique
CDRs.
[0228] In some embodiments, the anti-IL-6R antibody is a Fab, Fab',
F(ab').sub.2, Fv, scFv, (scFv).sub.2, single chain antibody
molecule, dual variable domain antibody, single variable domain
antibody, linear antibody, or V domain antibody.
[0229] In some embodiments, the anti-IL-6R antibody comprises a
scaffold. In certain embodiments, the scaffold is Fc, optionally
human Fc. In some embodiments, the anti-IL-6R antibody comprises a
heavy chain constant region of a class selected from IgG, IgA, IgD,
IgE, and IgM. In certain embodiments, the anti-IL-6R antibody
comprises a heavy chain constant region of the class IgG and a
subclass selected from IgG1, IgG2, IgG3, and IgG4.
[0230] In some embodiments, the IL-6 antagonist is immunoconjugate
or fusion protein comprising an IL-6R antigen-binding fragment.
[0231] In some embodiments, the antibody is bispecific or
multispecific, with at least one of the antigen-binding portions
having specificity for IL-6 receptor.
[0232] In some embodiments, the antibody is fully human. In some
embodiments, the antibody is humanized. In some embodiments, the
antibody is chimeric and has non-human V regions and human C region
domains. In some embodiments, the antibody is murine.
[0233] In typical embodiments, the anti-IL-6R antibody has a
K.sub.D for binding human IL-6 receptor of less than 100 nM. In
some embodiments, the anti-IL-6R antibody has a K.sub.D for binding
human IL-6 receptor of less than 75 nM, 50 nM, 25 nM, 20 nM, 15 nM,
or 10 nM. In particular embodiments, the anti-IL-6R antibody has a
K.sub.D for binding human IL-6 receptor of less than 5 nM, 4 nM, 3
nM, or 2 nM. In selected embodiments, the anti-IL-6R antibody has a
K.sub.D for binding human IL-6 receptor of less than 1 nM, 750 pM,
or 500 pM. In specific embodiments, the anti-IL-6R antibody has a
K.sub.D for binding human IL-6 receptor of no more than 500 pM, 400
pM, 300 pM, 200 pM, or 100 pM.
[0234] In typical embodiments, the anti-IL-6R antibody has an
elimination half-life following intravenous administration of at
least 7 days. In certain embodiments, the anti-IL-6R antibody has
an elimination half-life of at least 14 days, at least 21 days, or
at least 30 days.
[0235] In some embodiments, the anti-IL-6R antibody has a human IgG
constant region with at least one amino acid substitution that
extends serum half-life as compared to the unsubstituted human IgG
constant domain.
[0236] In certain embodiments, the IgG constant domain comprises
substitutions at residues 252, 254, and 256, wherein the amino acid
substitution at amino acid residue 252 is a substitution with
tyrosine, the amino acid substitution at amino acid residue 254 is
a substitution with threonine, and the amino acid substitution at
amino acid residue 256 is a substitution with glutamic acid
("YTE"). See U.S. Pat. No. 7,083,784, incorporated herein by
reference in its entirety. In certain extended half-life
embodiments, the IgG constant domain comprises substitutions
selected from T250Q/M428L (Hinton et al., J. Immunology 176:346-356
(2006)); N434A (Yeung et al., J. Immunology 182:7663-7671 (2009));
or T307A/E380A/N434A (Petkova et al., International Immunology, 18:
1759-1769 (2006)).
[0237] In some embodiments, the elimination half-life of the
anti-IL-6R antibody is increased by utilizing the FcRN-binding
properties of human serum albumin. In certain embodiments, the
antibody is conjugated to albumin (Smith et al., Bioconjug. Chem.,
12: 750-756 (2001)). In some embodiments, the anti-IL-6R antibody
is fused to bacterial albumin-binding domains (Stork et al., Prot.
Eng. Design Science 20: 569-76 (2007)). In some embodiments, the
anti-IL-6R antibody is fused to an albumin-binding peptide (Nguygen
et al., Prot Eng Design Sel 19: 291-297 (2006)). In some
embodiments, the anti-IL-6R antibody is bispecific, with one
specificity being to IL-6 receptor, and one specificity being to
human serum albumin (Ablynx, WO 2006/122825 (bispecific
Nanobody)).
[0238] In some embodiments, the elimination half-life of the
anti-IL-6R antibody is increased by PEGylation (Melmed et al.,
Nature Reviews Drug Discovery 7: 641-642 (2008)); by HPMA copolymer
conjugation (Lu et al., Nature Biotechnology 17: 1101-1104 (1999));
by dextran conjugation (Nuclear Medicine Communications, 16:
362-369 (1995)); by conjugation with homo-amino-acid polymers
(HAPs; HAPylation) (Schlapschy et al., Prot Eng Design Sel 20:
273-284 (2007)); or by polysialylation (Constantinou et al.,
Bioconjug. Chem. 20: 924-931 (2009)).
[0239] 2.7.2.1. Tocilizumab and Derivatives
[0240] In certain embodiments, the anti-IL-6R antibody or
antigen-binding portion thereof comprises all six CDRs of
tocilizumab. In particular embodiments, the antibody or
antigen-binding portion thereof comprises the tocilizumab heavy
chain V region and light chain V region. In specific embodiments,
the antibody is the full-length tocilizumab antibody.
[0241] In various embodiments, the anti-IL-6R antibody is a
derivative of tocilizumab.
[0242] In some embodiments, the tocilizumab derivative includes one
or more amino acid substitutions in the tocilizumab heavy and/or
light chain V regions.
[0243] In certain embodiments, the tocilizumab derivative comprises
fewer than 25 amino acid substitutions, fewer than 20 amino acid
substitutions, fewer than 15 amino acid substitutions, fewer than
10 amino acid substitutions, fewer than 5 amino acid substitutions,
fewer than 4 amino acid substitutions, fewer than 3 amino acid
substitutions, fewer than 2 amino acid substitutions, or 1 amino
acid substitution relative to the original V.sub.H and/or V.sub.L
of the tocilizumab anti-IL-6R antibody, while retaining specificity
for human IL-6 receptor.
[0244] In certain embodiments, the tocilizumab derivative comprises
an amino acid sequence that is at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, at least 90%, at least 95%, or at least
99% identical to the amino acid sequence of the V.sub.H and V.sub.L
domain of tocilizumab. The percent sequence identity is determined
using BLAST algorithms using default parameters.
[0245] In certain embodiments, the tocilizumab derivative comprises
an amino acid sequence in which the CDRs comprise an amino acid
sequence that is at least 45%, at least 50%, at least 55%, at least
60%, at least 65%, at least 70%, at least 75%, at least 80%, at
least 85%, at least 90%, at least 95%, or at least 99% identical to
the amino acid sequence of the respective CDRs of tocilizumab. The
percent sequence identity is determined using BLAST algorithms
using default parameters.
[0246] In certain embodiments, the V.sub.H and/or V.sub.L CDR
derivatives comprise conservative amino acid substitutions at one
or more predicted nonessential amino acid residues (i.e., amino
acid residues which are not critical for the antibody to
specifically bind to human IL-6 receptor).
[0247] 2.7.2.2. Sarilumab and Derivatives
[0248] In certain embodiments, the anti-IL-6R antibody or
antigen-binding portion thereof comprises all six CDRs of
sarilumab. In particular embodiments, the antibody or
antigen-binding portion thereof comprises the sarilumab heavy chain
V region and light chain V region. In specific embodiments, the
antibody is the full-length sarilumab antibody.
[0249] In various embodiments, the anti-IL-6R antibody is a
derivative of sarilumab.
[0250] In some embodiments, the sarilumab derivative includes one
or more amino acid substitutions in the sarilumab heavy and/or
light chain V regions.
[0251] In certain embodiments, the sarilumab derivative comprises
fewer than 25 amino acid substitutions, fewer than 20 amino acid
substitutions, fewer than 15 amino acid substitutions, fewer than
10 amino acid substitutions, fewer than 5 amino acid substitutions,
fewer than 4 amino acid substitutions, fewer than 3 amino acid
substitutions, fewer than 2 amino acid substitutions, or 1 amino
acid substitution relative to the original V.sub.H and/or V.sub.L
of the sarilumab anti-IL-6R antibody, while retaining specificity
for human IL-6 receptor.
[0252] In certain embodiments, the sarilumab derivative comprises
an amino acid sequence that is at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, at least 90%, at least 95%, or at least
99% identical to the amino acid sequence of the V.sub.H and V.sub.L
domain of sarilumab. The percent sequence identity is determined
using BLAST algorithms using default parameters.
[0253] In certain embodiments, the sarilumab derivative comprises
an amino acid sequence in which the CDRs comprise an amino acid
sequence that is at least 45%, at least 50%, at least 55%, at least
60%, at least 65%, at least 70%, at least 75%, at least 80%, at
least 85%, at least 90%, at least 95%, or at least 99% identical to
the amino acid sequence of the respective CDRs of sarilumab. The
percent sequence identity is determined using BLAST algorithms
using default parameters.
[0254] In certain embodiments, the V.sub.H and/or V.sub.L CDR
derivatives comprise conservative amino acid substitutions at one
or more predicted nonessential amino acid residues (i.e., amino
acid residues which are not critical for the antibody to
specifically bind to human IL-6 receptor).
[0255] 2.7.2.3. Vobarilizumab and Derivatives
[0256] In certain embodiments, the anti-IL-6R antibody or
antigen-binding portion thereof comprises all six CDRs of
vobarilizumab. In particular embodiments, the antibody or
antigen-binding portion thereof comprises the vobarilizumab heavy
chain V region and light chain V region. In specific embodiments,
the antibody is the full-length vobarilizumab antibody.
[0257] In various embodiments, the anti-IL-6R antibody is a
derivative of vobarilizumab.
[0258] In some embodiments, the vobarilizumab derivative includes
one or more amino acid substitutions in the vobarilizumab heavy
and/or light chain V regions.
[0259] In certain embodiments, the vobarilizumab derivative
comprises fewer than 25 amino acid substitutions, fewer than 20
amino acid substitutions, fewer than 15 amino acid substitutions,
fewer than 10 amino acid substitutions, fewer than 5 amino acid
substitutions, fewer than 4 amino acid substitutions, fewer than 3
amino acid substitutions, fewer than 2 amino acid substitutions, or
1 amino acid substitution relative to the original V.sub.H and/or
V.sub.L of the vobarilizumab anti-IL-6R antibody, while retaining
specificity for human IL-6 receptor.
[0260] In certain embodiments, the vobarilizumab derivative
comprises an amino acid sequence that is at least 45%, at least
50%, at least 55%, at least 60%, at least 65%, at least 70%, at
least 75%, at least 80%, at least 85%, at least 90%, at least 95%,
or at least 99% identical to the amino acid sequence of the V.sub.H
and V.sub.L domain of vobarilizumab. The percent sequence identity
is determined using BLAST algorithms using default parameters.
[0261] In certain embodiments, the vobarilizumab derivative
comprises an amino acid sequence in which the CDRs comprise an
amino acid sequence that is at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, at least 90%, at least 95%, or at least
99% identical to the amino acid sequence of the respective CDRs of
vobarilizumab. The percent sequence identity is determined using
BLAST algorithms using default parameters.
[0262] In certain embodiments, the V.sub.H and/or V.sub.L CDR
derivatives comprise conservative amino acid substitutions at one
or more predicted nonessential amino acid residues (i.e., amino
acid residues which are not critical for the antibody to
specifically bind to human IL-6 receptor).
[0263] 2.7.2.4. Other Anti-IL-6R Antibodies and Derivatives
[0264] In certain embodiments, the anti-IL-6R antibody or
antigen-binding portion thereof comprises all six CDRs of an
antibody selected from the group consisting of: SA237 (Roche),
NI-1201 (NovImmune), and an antibody described in US 2012/0225060.
In particular embodiments, the antibody or antigen-binding portion
thereof comprises the heavy chain V region and light chain V region
of an antibody selected from the group consisting of: SA237
(Roche), NI-1201 (NovImmune), and an antibody described in US
2012/0225060. In specific embodiments, the antibody is a
full-length selected from the group consisting of: SA237 (Roche),
NI-1201 (NovImmune), and an antibody described in US
2012/0225060.
[0265] In various embodiments, the anti-IL-6R antibody is a
derivative of an antibody selected from the group consisting of:
SA237 (Roche), NI-1201 (NovImmune), or an antibody described in US
2012/0225060.
[0266] 2.7.3. Anti-IL-6:IL-6R Complex Antibodies
[0267] In various embodiments, the IL-6 antagonist is an antibody
specific for the complex of IL-6 and IL-6R. In certain embodiments,
the antibody has the six CDRs of an antibody selected from those
described in US 2011/0002936, which is incorporated herein by
reference in its entirety.
[0268] 2.7.4. JAK and STAT Inhibitors
[0269] In various embodiments, the IL-6 antagonist is an inhibitor
of the JAK signaling pathway. In some embodiments, the JAK
inhibitor is a JAK1-specific inhibitor. In some embodiments, the
JAK inhibitor is a JAK3-specific inhibitor. In some embodiments,
the JAK inhibitor is a pan-JAK inhibitor.
[0270] In certain embodiments, the JAK inhibitor is selected from
the group consisting of tofacitinib (Xeljanz), decernotinib,
ruxolitinib, upadacitinib, baricitinib, filgotinib, lestaurtinib,
pacritinib, peficitinib, INCB-039110, ABT-494, INCB-047986 and
AC-410.
[0271] In various embodiments, the IL-6 antagonist is a STAT3
inhibitor. In a specific embodiment, the inhibitor is AZD9150
(AstraZeneca, Isis Pharmaceuticals), a STAT3 antisense
molecule.
[0272] 2.7.5. Additional IL-6 Antagonists
[0273] In various embodiments, the IL-6 antagonist is an antagonist
peptide.
[0274] In certain embodiments, the IL-6 antagonist is C326 (an IL-6
inhibitor by Avidia, also known as AMG220), or FE301, a recombinant
protein inhibitor of IL-6 (Ferring International Center S.A.,
Conaris Research Institute AG). In some embodiments, the anti-IL-6
antagonist comprises soluble gp130, FE301 (Conaris/Ferring).
[0275] 2.8. Pharmaceutical Composition
[0276] The IL-6 antagonists used in the methods described herein
can be formulated in any appropriate pharmaceutical composition for
administration by any suitable route of administration. Suitable
routes of administration include, but are not limited to, the
intravitreal, intraarterial, intradermal, intramuscular,
intraperitoneal, intravenous, nasal, parenteral, pulmonary, and
subcutaneous routes.
[0277] The pharmaceutical composition may comprise one or more
pharmaceutical excipients. Any suitable pharmaceutical excipient
may be used, and one of ordinary skill in the art is capable of
selecting suitable pharmaceutical excipients. Accordingly, the
pharmaceutical excipients provided below are intended to be
illustrative, and not limiting. Additional pharmaceutical
excipients include, for example, those described in the Handbook of
Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009),
incorporated by reference in its entirety.
[0278] 2.9. Dosage Regimens
[0279] The IL-6 antagonist is administered at a dose sufficient to
reduce inflammation without causing immune suppression.
[0280] 2.9.1. Antibodies, Antigen-Binding Fragments, Peptides
[0281] In typical embodiments, antibody, antigen-binding fragments,
and peptide IL-6 antagonists are administered parenterally.
[0282] In some parenteral embodiments, the IL-6 antagonist is
administered intravenously. In certain intravenous embodiments, the
IL-6 antagonist is administered as a bolus. In certain intravenous
embodiments, the IL-6 antagonist is administered as an infusion. In
certain intravenous embodiments, the IL-6 antagonist is
administered as a bolus followed by infusion.
[0283] In some parenteral embodiments, the IL-6 antagonist is
administered subcutaneously.
[0284] In various embodiments, the antibody, antigen-binding
fragment, or peptide IL-6 antagonist is administered in a dose that
is independent of patient weight or surface area (flat dose).
[0285] In some embodiments, the intravenous flat dose is 0.1 mg,
0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or
1 mg. In some embodiments, the intravenous flat dose is 1 mg, 2 mg,
3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some
embodiments, the intravenous flat dose is 11 mg, 12 mg, 13 mg, 14
mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some
embodiments, the intravenous flat dose is 25 mg, 30 mg, 40 mg, or
50 mg. In some embodiments, the intravenous flat dose is 60 mg, 70
mg, 80 mg, 90 mg, or 100 mg. In some embodiments, the intravenous
flat dose is 200 mg, 300 mg, 400 mg, or 500 mg. In some
embodiments, the intravenous flat dose is 0.1-1 mg, 1-10 mg, 10-15
mg, 15-20 mg, 20-30 mg, 30-40 mg, or 40-50 mg. In some embodiments,
the intravenous flat dose is 1-50 mg, 50-100 mg, or 100 mg 500
mg.
[0286] In some embodiments, the subcutaneous flat dose is 0.1 mg,
0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or
1 mg. In some embodiments, the subcutaneous flat dose is 1 mg, 2
mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some
embodiments, the subcutaneous flat dose is 11 mg, 12 mg, 13 mg, 14
mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some
embodiments, the subcutaneous flat dose is 25 mg, 30 mg, 40 mg, or
50 mg. In some embodiments, the subcutaneous flat dose is 60 mg, 70
mg, 80 mg, 90 mg, or 100 mg. In some embodiments, the subcutaneous
flat dose is 200 mg, 300 mg, 400 mg, or 500 mg. In some
embodiments, the subcutaneous flat dose is 0.1-1 mg, 1-10 mg, 10-15
mg, 15-20 mg, 20-30 mg, 30-40 mg, or 40-50 mg. In some embodiments,
the subcutaneous flat dose is 1-50 mg, 50-100 mg, or 100 mg-500
mg.
[0287] In various embodiments, the antibody, antigen-binding
fragment, or peptide IL-6 antagonist is administered as a patient
weight-based dose.
[0288] In some embodiments, the antagonist is administered at an
intravenous dose of 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg,
0.05 mg/kg, 0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg or 0.1
mg/kg. In some embodiments, the antagonist is administered at an
intravenous dose of 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5
mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg or 1.0 mg/kg. In
some embodiments, the antagonist is administered at an intravenous
dose of 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg,
4.5 mg/kg, or 5 mg/kg.
[0289] In some embodiments, the antagonist is administered at a
subcutaneous dose of 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04
mg/kg, 0.05 mg/kg, 0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg
or 0.1 mg/kg. In some embodiments, the antagonist is administered
at a subcutaneous dose of 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4
mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg or 1.0
mg/kg. In some embodiments, the antagonist is administered at a
subcutaneous dose of 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5
mg/kg, 4 mg/kg, 4.5 mg/kg, or 5 mg/kg.
[0290] In various intravenous embodiments, the IL-6 antagonist is
administered once every 7 days, once every 14 days, once every 21
days, once every 28 days, or once a month. In various subcutaneous
embodiments, the IL-6 antagonist is administered once every 14
days, once every 28 days, once a month, once every two months
(every other month), or once every three months.
[0291] 2.9.2. Small Molecule Inhibitors
[0292] In typical embodiments, small molecule JAK inhibitors and
STAT inhibitors are administered orally.
[0293] In various embodiments, the inhibitor is administered once
or twice a day at an oral dose of 0.1-1 mg, 1-10 mg, 10-20 mg,
20-30 mg, 30-40 mg, or 40-50 mg. In some embodiments, the inhibitor
is administered once or twice a day at a dose of 50-60 mg, 60-70
mg, 70-80 mg, 80-90 mg, or 90-100 mg. In some embodiments, the
inhibitor is administered at a dose of 0.1, 0.5, 1, 2, 5, 10, 15,
20, 25, 30, 35, 40, 45, or 50 mg PO once or twice a day. In some
embodiments, the inhibitor is administered at a dose of 75 mg or
100 mg PO once or twice a day.
[0294] 2.9.3. Monthly Equivalent Dose
[0295] In typical embodiments, the IL-6 antagonist is administered
at a monthly equivalent dose that is less than the monthly
equivalent dose for treating rheumatoid arthritis with the same
IL-6 antagonist. "Monthly equivalent dose" is the calculated total
dose administered per month, regardless of dose amount and dosage
schedule.
[0296] In some embodiments, the IL-6 antagonist is administered at
a monthly equivalent dose no more than 50% of a monthly equivalent
dose for treating rheumatoid arthritis with the same IL-6
antagonist. In various embodiments, the IL-6 antagonist is
administered at a monthly equivalent dose no more than 45%, 40%,
35%, 30%, 25%, 20%, 15%, 10%, or 5% of a monthly equivalent dose
for treating rheumatoid arthritis with the same IL-6 antagonist. In
certain embodiments, the IL-6 antagonist is administered at a
monthly equivalent dose no more than 45% of a monthly equivalent
dose for treating rheumatoid arthritis. In certain embodiments, the
IL-6 antagonist is administered at a monthly equivalent dose no
more than 40% of a monthly equivalent dose for treating rheumatoid
arthritis. In certain embodiments, the IL-6 antagonist is
administered at a monthly equivalent dose no more than 30% of a
monthly equivalent dose for treating rheumatoid arthritis. In
certain embodiments, the IL-6 antagonist is administered at a
monthly equivalent dose no more than 25% of a monthly equivalent
dose for treating rheumatoid arthritis. In certain embodiments, the
IL-6 antagonist is administered at a monthly equivalent dose no
more than 20% of a monthly equivalent dose for treating rheumatoid
arthritis. In certain embodiments, the IL-6 antagonist is
administered at a monthly equivalent dose no more than 15% of a
monthly equivalent dose for treating rheumatoid arthritis. In
certain embodiments, the IL-6 antagonist is administered at a
monthly equivalent dose no more than 10% of a monthly equivalent
dose for treating rheumatoid arthritis. In certain embodiments, the
IL-6 antagonist is administered at a monthly equivalent dose no
more than 5% of a monthly equivalent dose for treating rheumatoid
arthritis.
[0297] In various embodiments, the IL-6 antagonist is administered
at a monthly equivalent dose about 50%, 45%, 40%, 35%, 30%, 25%,
20%, 15%, 10%, or 5% of a monthly equivalent dose for treating
rheumatoid arthritis with the same IL-6 antagonist. In certain
embodiments, the IL-6 antagonist is administered at a monthly
equivalent dose about 50% of a monthly equivalent dose for treating
rheumatoid arthritis. In certain embodiments, the IL-6 antagonist
is administered at a monthly equivalent dose about 40% of a monthly
equivalent dose for treating rheumatoid arthritis. In certain
embodiments, the IL-6 antagonist is administered at a monthly
equivalent dose about 30% of a monthly equivalent dose for treating
rheumatoid arthritis. In certain embodiments, the IL-6 antagonist
is administered at a monthly equivalent dose about 25% of a monthly
equivalent dose for treating rheumatoid arthritis. In certain
embodiments, the IL-6 antagonist is administered at a monthly
equivalent dose about 20% of a monthly equivalent dose for treating
rheumatoid arthritis. In certain embodiments, the IL-6 antagonist
is administered at a monthly equivalent dose about 15% of a monthly
equivalent dose for treating rheumatoid arthritis. In certain
embodiments, the IL-6 antagonist is administered at a monthly
equivalent dose about 10% of a monthly equivalent dose for treating
rheumatoid arthritis. In certain embodiments, the IL-6 antagonist
is administered at a monthly equivalent dose about 5% of a monthly
equivalent dose for treating rheumatoid arthritis.
[0298] In some embodiments, the IL-6 antagonist is the COR-001
antibody. In various embodiments, COR-001 is administered
intravenously at a monthly equivalent dose of 0.5-50 mg, such as
0.5-1 mg, 0.5-2 mg, 0.5-5 mg, 0.5-10 mg, 0.5-20 mg, 0.5-30 mg,
0.5-40 mg, 1-2 mg, 1-5 mg, 1-10 mg, 1-20 mg, 1-30 mg, 1-40 mg, 1-50
mg, 2-5 mg, 2-10 mg, 2-20 mg, 2-30 mg, 2-40 mg, 2-50 mg, 5-10 mg,
5-20 mg, 5-30 mg, 5-40 mg, 5-50 mg, 10-20 mg, 10-30 mg, 10-40 mg,
10-50 mg, 20-30 mg, 20-40 mg, 20-50 mg, 30-40 mg, 30-50 mg, or
40-50 mg. In certain preferred embodiments, COR-001 is administered
intravenously at a monthly equivalent dose of 2-40 mg.
[0299] In various embodiments, COR-001 is administered
intravenously at a monthly equivalent dose of about 0.5 mg, 1 mg, 2
mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg,
40 mg, or 50 mg. In certain embodiments, COR-001 is administered
intravenously at a monthly equivalent dose of about 1 mg. In
certain embodiments, COR-001 is administered intravenously at a
monthly equivalent dose of about 2 mg. In certain embodiments,
COR-001 is administered intravenously at a monthly equivalent dose
of about 3 mg. In certain embodiments, COR-001 is administered
intravenously at a monthly equivalent dose of about 4 mg. In
certain embodiments, COR-001 is administered intravenously at a
monthly equivalent dose of about 5 mg. In certain embodiments,
COR-001 is administered intravenously at a monthly equivalent dose
of about 6 mg. In certain embodiments, COR-001 is administered
intravenously at a monthly equivalent dose of about 10 mg. In
certain embodiments, COR-001 is administered intravenously at a
monthly equivalent dose of about 12 mg. In certain embodiments,
COR-001 is administered intravenously at a monthly equivalent dose
of about 15 mg. In certain embodiments, COR-001 is administered
intravenously at a monthly equivalent dose of about 20 mg. In
certain embodiments, COR-001 is administered intravenously at a
monthly equivalent dose of about 40 mg.
[0300] In various embodiments, COR-001 is administered
subcutaneously at a monthly equivalent dose of 1-100 mg, such as
1-2 mg, 1-5 mg, 1-10 mg, 1-20 mg, 1-30 mg, 1-40 mg, 1-50 mg, 1-70
mg, 1-100 mg, 2-5 mg, 2-10 mg, 2-20 mg, 2-30 mg, 2-40 mg, 2-50 mg,
2-70 mg, 2-100 mg, 3-5 mg, 3-10 mg, 3-20 mg, 3-30 mg, 3-40 mg, 3-50
mg, 3-70 mg, 3-100 mg, 5-10 mg, 5-20 mg, 5-30 mg, 5-40 mg, 5-50 mg,
5-70 mg, 5-100 mg, 10-20 mg, 10-30 mg, 10-40 mg, 10-50 mg, 10-70
mg, 10-100 mg, 20-30 mg, 20-40 mg, 20-50 mg, 20-70 mg, 20-100 mg,
30-40 mg, 30-50 mg, 30-70 mg, 30-100 mg, or 40-100 mg. In certain
preferred embodiments, COR-001 is administered subcutaneously at a
monthly equivalent dose of 3-70 mg.
[0301] In various embodiments, COR-001 is administered
subcutaneously at a monthly equivalent dose of about 0.5 mg, 1 mg,
2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30
mg, 40 mg, 50 mg, 70 mg, or 100 mg. In certain embodiments, COR-001
is administered subcutaneously at a monthly equivalent dose of
about 1 mg. In certain embodiments, COR-001 is administered
subcutaneously at a monthly equivalent dose of about 2 mg. In
certain embodiments, COR-001 is administered subcutaneously at a
monthly equivalent dose of about 3 mg. In certain embodiments,
COR-001 is administered subcutaneously at a monthly equivalent dose
of about 4 mg. In certain embodiments, COR-001 is administered
subcutaneously at a monthly equivalent dose of about 5 mg. In
certain embodiments, COR-001 is administered subcutaneously at a
monthly equivalent dose of about 6 mg. In certain embodiments,
COR-001 is administered subcutaneously at a monthly equivalent dose
of about 10 mg. In certain embodiments, COR-001 is administered
subcutaneously at a monthly equivalent dose of about 12 mg. In
certain embodiments, COR-001 is administered subcutaneously at a
monthly equivalent dose of about 15 mg. In certain embodiments,
COR-001 is administered subcutaneously at a monthly equivalent dose
of about 17 mg. In certain embodiments, COR-001 is administered
subcutaneously at a monthly equivalent dose of about 20 mg. In
certain embodiments, COR-001 is administered subcutaneously at a
monthly equivalent dose of about 35 mg. In certain embodiments,
COR-001 is administered subcutaneously at a monthly equivalent dose
of about 40 mg. In certain embodiments, COR-001 is administered
subcutaneously at a monthly equivalent dose of about 70 mg. In
certain embodiments, COR-001 is administered subcutaneously at a
monthly equivalent dose of about 100 mg.
[0302] In some embodiments, the IL-6 antagonist is siltuximab. In
various embodiments, siltuximab is administered intravenously at a
monthly equivalent dose of 10-500 mg, such as 10-20 mg, 10-30 mg,
10-40 mg, 10-50 mg, 10-100 mg, 10-150 mg, 10-200 mg, 10-300 mg,
10-400 mg, 20-30 mg, 20-40 mg, 20-50 mg, 20-100 mg, 20-150 mg,
20-200 mg, 20-300 mg, 20-400 mg, 20-500 mg, 30-40 mg, 30-50 mg,
30-100 mg, 30-150 mg, 30-200 mg, 30-300 mg, 30-400 mg, 30-500 mg,
40-50 mg, 40-100 mg, 40-150 mg, 40-200 mg, 40-250 mg, 40-300 mg,
40-400 mg, 40-500 mg, 50-100 mg, 50-150 mg, 50-200 mg, 50-300 mg,
50-400 mg, 50-500 mg, 100-150 mg, 100-200 mg, 100-300 mg, 100-400
mg, 100-500 mg, 150-200 mg, 150-300 mg, 150-400 mg, 150-500 mg,
200-300 mg, 200-400 mg, 200-500 mg, 300-400 mg, 300-500 mg, or
400-500 mg. In certain preferred embodiments, siltuximab is
administered intravenously at a monthly equivalent dose of 50-500
mg. In various embodiments, siltuximab is administered
intravenously at a monthly equivalent dose of about 10 mg, 20 mg,
30 mg, 40 mg, 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, or 500
mg. In certain embodiments, siltuximab is administered
intravenously at a monthly equivalent dose of about 50 mg. In
certain embodiments, siltuximab is administered intravenously at a
monthly equivalent dose of about 100 mg. In certain embodiments,
siltuximab is administered intravenously at a monthly equivalent
dose of about 150 mg. In certain embodiments, siltuximab is
administered intravenously at a monthly equivalent dose of about
200 mg. In certain embodiments, siltuximab is administered
intravenously at a monthly equivalent dose of about 300 mg. In
certain embodiments, siltuximab is administered intravenously at a
monthly equivalent dose of about 500 mg.
[0303] In various embodiments, siltuximab is administered
subcutaneously at a monthly equivalent dose of 50-1000 mg, such as
50-80 mg, 50-100 mg, 50-160 mg, 50-200 mg, 50-240 mg, 50-320 mg,
50-480 mg, 50-800 mg, 80-100 mg, 80-160 mg, 80-200 mg, 80-240 mg,
80-320 mg, 80-480 mg, 80-800 mg, 80-1000 mg, 100-160 mg, 100-200
mg, 100-240 mg, 100-320 mg, 100-480 mg, 100-800 mg, 100-1000 mg,
160-200 mg, 160-240 mg, 160-320 mg, 160-480 mg, 160-800 mg,
160-1000 mg, 200-240 mg, 200 320 mg, 200-480 mg, 200-800 mg,
200-1000 mg, 240-320 mg, 240-480 mg, 240-800 mg, 240-1000 mg,
320-480 mg, 320-800 mg, 320-1000 mg, 480-800 mg, 480-1000 mg, or
800-1000 mg. In certain preferred embodiments, siltuximab is
administered subcutaneously at a monthly equivalent dose of 80-800
mg. In various embodiments, siltuximab is administered
subcutaneously at a monthly equivalent dose of about 50 mg, 80 mg.
100 mg, 160 mg, 240 mg. 320 mg, 480 mg. 800 mg, or 1000 mg. In
certain embodiments, siltuximab is administered subcutaneously at a
monthly equivalent dose of about 50 mg. In certain embodiments,
siltuximab is administered subcutaneously at a monthly equivalent
dose of about 80 mg. In certain embodiments, siltuximab is
administered subcutaneously at a monthly equivalent dose of about
100 mg. In certain embodiments, siltuximab is administered
subcutaneously at a monthly equivalent dose of about 160 mg. In
certain embodiments, siltuximab is administered subcutaneously at a
monthly equivalent dose of about 240 mg. In certain embodiments,
siltuximab is administered subcutaneously at a monthly equivalent
dose of about 320 mg. In certain embodiments, siltuximab is
administered subcutaneously at a monthly equivalent dose of about
480 mg. In certain embodiments, siltuximab is administered
subcutaneously at a monthly equivalent dose of about 800 mg. In
certain embodiments, siltuximab is administered subcutaneously at a
monthly equivalent dose of about 1000 mg.
[0304] In some embodiments, the IL-6 antagonist is gerilimzumab. In
various embodiments, gerilimzumab is administered intravenously at
a monthly equivalent dose of 0.05-2 mg, such as 0.05-0.075 mg,
0.05-0.1 mg, 0.05-0.12 mg, 0.05-0.3 mg, 0.05-0.6 mg, 0.05-0.9 mg,
0.05-1.8 mg, 0.075-0.1 mg, 0.075-0.12 mg, 0.075-0.3 mg, 0.075-0.6
mg, 0.075-0.9 mg, 0.075-1.8 mg, 0.075-2 mg, 0.1-0.12 mg, 0.1-0.3
mg, 0.1-0.6 mg, 0.1-0.9 mg, 0.1-1.8 mg, 0.1-2 mg, 0.12-0.3 mg,
0.12-0.6 mg, 0.12-0.9 mg, 0.12-1.8 mg, 0.12-2 mg, 0.3-0.6 mg,
0.3-0.9 mg, 0.3-1.8 mg, 0.3-2 mg, 0.6-0.9 mg, 0.6-1.8 mg, 0.6-2 mg,
0.9-1.8 mg, 0.9-2 mg, or 1.8-2 mg. In certain preferred
embodiments, gerilimzumab is administered intravenously at a
monthly equivalent dose of 0.075-1.8 mg. In various embodiments,
gerilimzumab is administered intravenously at a monthly equivalent
dose of about 0.05 mg, 0.075 mg, 0.1 mg, 0.12 mg, 0.3 mg, 0.6 mg,
0.9 mg, 1.8 mg, or 2 mg. In certain embodiments, gerilimzumab is
administered intravenously at a monthly equivalent dose of about
0.05 mg. In certain embodiments, gerilimzumab is administered
intravenously at a monthly equivalent dose of about 0.075 mg. In
certain embodiments, gerilimzumab is administered intravenously at
a monthly equivalent dose of about 0.1 mg. In certain embodiments,
gerilimzumab is administered intravenously at a monthly equivalent
dose of about 0.12 mg. In certain embodiments, gerilimzumab is
administered intravenously at a monthly equivalent dose of about
0.3 mg. In certain embodiments, gerilimzumab is administered
intravenously at a monthly equivalent dose of about 0.6 mg. In
certain embodiments, gerilimzumab is administered intravenously at
a monthly equivalent dose of about 0.9 mg. In certain embodiments,
gerilimzumab is administered intravenously at a monthly equivalent
dose of about 1.8 mg. In certain embodiments, gerilimzumab is
administered intravenously at a monthly equivalent dose of about 2
mg.
[0305] In various embodiments, gerilimzumab is administered
subcutaneously at a monthly equivalent dose of 0.1-5 mg, such as
0.1-0.125 mg, 0.1-0.15 mg, 0.1-0.2 mg, 0.1-0.5 mg, 0.1-1 mg,
0.1-1.5 mg, 0.1-2 mg, 0.1-3 mg, 0.1-4 mg, 0.125-0.15 mg, 0.125-0.2
mg, 0.125-0.5 mg, 0.125-1 mg, 0.125-1.5 mg, 0.125-2 mg, 0.125-3 mg,
0.125-4 mg, 0.125-5 mg, 0.15-0.2 mg, 0.15-0.5 mg, 0.15-1 mg,
0.15-1.5 mg, 0.15-2 mg, 0.15-3 mg, 0.15-4 mg, 0.15-5 mg, 0.2-0.5
mg, 0.2-1 mg, 0.2-1.5 mg, 0.2-2 mg, 0.2-3 mg, 0.2-4 mg, 0.2-5 mg,
0.5-1 mg, 0.5-1.5 mg, 0.5-2 mg, 0.5-3 mg, 0.5-4 mg, 0.5-5 mg, 1-1.5
mg, 1-2 mg, 1-3 mg, 1-4 mg, 1-5 mg, 1.5-2 mg, 1.5-3 mg, 1.5-4 mg,
1.5-5 mg, 2-3 mg, 2-4 mg, 2-5 mg, 3-4 mg, 3-5 mg, or 4-5 mg. In
certain preferred embodiments, gerilimzumab is administered
subcutaneously at a monthly equivalent dose of 0.125-3 mg. In
various embodiments, gerilimzumab is administered subcutaneously at
a monthly equivalent dose of about 0.1 mg, 0.125 mg, 0.15 mg, 0.2
mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, or 5 mg. In certain
embodiments, gerilimzumab is administered subcutaneously at a
monthly equivalent dose of about 0.125 mg. In certain embodiments,
gerilimzumab is administered subcutaneously at a monthly equivalent
dose of about 0.2 mg. In certain embodiments, gerilimzumab is
administered subcutaneously at a monthly equivalent dose of about
0.5 mg. In certain embodiments, gerilimzumab is administered
subcutaneously at a monthly equivalent dose of about 1 mg. In
certain embodiments, gerilimzumab is administered subcutaneously at
a monthly equivalent dose of about 1.5 mg. In certain embodiments,
gerilimzumab is administered subcutaneously at a monthly equivalent
dose of about 3 mg.
[0306] In some embodiments, the IL-6 antagonist is sirukumab. In
various embodiments, sirukumab is administered intravenously at a
monthly equivalent dose of 1-80 mg, such as 1-1.5 mg, 1-3 mg, 1-6
mg, 1-12 mg, 1-36 mg, 1-60 mg, 1.5-3 mg, 1.5-6 mg, 1.5-12 mg,
1.5-36 mg, 1.5-60 mg, 1.5-80 mg, 3-6 mg, 3-12 mg, 3-36 mg, 3-60 mg,
3-80 mg, 6-12 mg, 6-36 mg, 6-60 mg, 6-80 mg, 12-36 mg, 12-60 mg,
12-80 mg, 36-60 mg, 36-80 mg, or 60-80 mg. In certain preferred
embodiments, sirukumab is administered intravenously at a monthly
equivalent dose of 1.5-60 mg. In various embodiments, sirukumab is
administered intravenously at a monthly equivalent dose of about 1
mg, 1.5 mg, 3 mg, 6 mg, 12 mg, 36 mg, 60 mg, or 80 mg. In certain
embodiments, sirukumab is administered intravenously at a monthly
equivalent dose of about 1 mg. In certain embodiments, sirukumab is
administered intravenously at a monthly equivalent dose of about
1.5 mg. In certain embodiments, sirukumab is administered
intravenously at a monthly equivalent dose of about 3 mg. In
certain embodiments, sirukumab is administered intravenously at a
monthly equivalent dose of about 6 mg. In certain embodiments,
sirukumab is administered intravenously at a monthly equivalent
dose of about 12 mg. In certain embodiments, sirukumab is
administered intravenously at a monthly equivalent dose of about 36
mg. In certain embodiments, sirukumab is administered intravenously
at a monthly equivalent dose of about 60 mg. In certain
embodiments, sirukumab is administered intravenously at a monthly
equivalent dose of about 80 mg.
[0307] In various embodiments, sirukumab is administered
subcutaneously at a monthly equivalent dose of 1-100 mg, such as
1-2.5 mg, 1-5 mg, 1-10 mg, 1-20 mg, 1-30 mg, 1-40 mg, 1-50 mg, 1-60
mg, 2.5-5 mg, 2.5-10 mg, 2.5-20 mg, 2.5-30 mg, 2.5-40 mg, 2.5-50
mg, 2.5-60 mg, 2.5-100 mg, 5-10 mg, 5-20 mg, 5-30 mg, 5-40 mg, 5-50
mg, 5-60 mg, 5-100 mg, 10-20 mg, 10-30 mg, 10-40 mg, 10-50 mg,
10-60 mg, 10-100 mg, 20-30 mg, 20-40 mg, 20-50 mg, 20-60 mg, 20-100
mg, 30-40 mg, 30-50 mg, 30-60 mg, 30-100 mg, 40-50 mg, 40-60 mg,
40-100 mg, 50-60 mg, 50-100 mg, or 60-100 mg. In certain preferred
embodiments, sirukumab is administered subcutaneously at a monthly
equivalent dose of 2.5-100 mg. In various embodiments, sirukumab is
administered subcutaneously at a monthly equivalent dose of about 1
mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 100
mg. In certain embodiments, sirukumab is administered
subcutaneously at a monthly equivalent dose of about 2.5 mg. In
certain embodiments, sirukumab is administered subcutaneously at a
monthly equivalent dose of about 5 mg. In certain embodiments,
sirukumab is administered subcutaneously at a monthly equivalent
dose of about 10 mg. In certain embodiments, sirukumab is
administered subcutaneously at a monthly equivalent dose of about
20 mg. In certain embodiments, sirukumab is administered
subcutaneously at a monthly equivalent dose of about 60 mg. In
certain embodiments, sirukumab is administered subcutaneously at a
monthly equivalent dose of about 100 mg.
[0308] In some embodiments, the IL-6 antagonist is clazakizumab. In
various embodiments, clazakizumab is administered intravenously at
a monthly equivalent dose of 1-80 mg, such as 1-3 mg, 1-6 mg, 1-12
mg, 1-24 mg, 1-36 mg, 1-60 mg, 3-6 mg, 3-12 mg, 3-24 mg, 3-36 mg,
3-60 mg, 3-80 mg, 6-12 mg, 6-24 mg, 6-36 mg, 6-60 mg, 6-80 mg,
12-24 mg, 12-36 mg, 12-60 mg, 12-80 mg, 24-36 mg, 24-60 mg, 24-80
mg, 36-60 mg, 36-80 mg, or 60-80 mg. In certain preferred
embodiments, clazakizumab is administered intravenously at a
monthly equivalent dose of 3-60 mg. In various embodiments,
clazakizumab is administered intravenously at a monthly equivalent
dose of about 1 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg, 60 mg or 80
mg. In certain embodiments, clazakizumab is administered
intravenously at a monthly equivalent dose of about 1 mg. In
certain embodiments, clazakizumab is administered intravenously at
a monthly equivalent dose of about 3 mg. In certain embodiments,
clazakizumab is administered intravenously at a monthly equivalent
dose of about 6 mg. In certain embodiments, clazakizumab is
administered intravenously at a monthly equivalent dose of about 12
mg. In certain embodiments, clazakizumab is administered
intravenously at a monthly equivalent dose of about 24 mg. In
certain embodiments, clazakizumab is administered intravenously at
a monthly equivalent dose of about 36 mg. In certain embodiments,
clazakizumab is administered intravenously at a monthly equivalent
dose of about 60 mg. In certain embodiments, clazakizumab is
administered intravenously at a monthly equivalent dose of about 80
mg.
[0309] In various embodiments, clazakizumab is administered
subcutaneously at a monthly equivalent dose of 1-100 mg, such as
1-2 mg, 1-5 mg, 1-10 mg, 1-20 mg, 1-30 mg, 1-40 mg, 1-50 mg, 1-60
mg, 2-5 mg, 2-10 mg, 2-20 mg, 2-30 mg, 2-40 mg, 2-50 mg, 2-60 mg,
2-100 mg, 5-10 mg, 5-20 mg, 5-30 mg, 5-40 mg, 5-50 mg, 5-60 mg,
5-100 mg, 10-20 mg, 10-30 mg, 10-40 mg, 10-50 mg, 10-60 mg, 10-100
mg, 20-30 mg, 20-40 mg, 20-50 mg, 20-60 mg, 20-100 mg, 30-40 mg,
30-50 mg, 30-60 mg, 30-100 mg, 40-50 mg, 40-60 mg, 40-100 mg, 50-60
mg, 50-100 mg, or 60-100 mg. In certain preferred embodiments,
clazakizumab is administered subcutaneously at a monthly equivalent
dose of 5-100 mg. In various embodiments, clazakizumab is
administered subcutaneously at a monthly equivalent dose of about 1
mg, 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 100
mg. In certain embodiments, clazakizumab is administered
subcutaneously at a monthly equivalent dose of about 5 mg. In
certain embodiments, clazakizumab is administered subcutaneously at
a monthly equivalent dose of about 10 mg. In certain embodiments,
clazakizumab is administered subcutaneously at a monthly equivalent
dose of about 20 mg. In certain embodiments, clazakizumab is
administered subcutaneously at a monthly equivalent dose of about
40 mg. In certain embodiments, clazakizumab is administered
subcutaneously at a monthly equivalent dose of about 60 mg. In
certain embodiments, clazakizumab is administered subcutaneously at
a monthly equivalent dose of about 100 mg.
[0310] In some embodiments, the IL-6 antagonist is olokizumab. In
various embodiments, olokizumab is administered intravenously at a
monthly equivalent dose of 1-80 mg, such as 1-1.8 mg, 1-3.6 mg, 1-9
mg, 1-18 mg, 1-45 mg, 1-60 mg, 1.8-3.6 mg, 1.8-9 mg, 1.8-18 mg,
1.8-45 mg, 1.8-60 mg, 1.8-80 mg, 3.6-9 mg, 3.6-18 mg, 3.6-45 mg,
3.6-60 mg, 3.6-80 mg, 9-18 mg, 9-45 mg, 9-60 mg, 9-80 mg, 18-45 mg,
18-60 mg, 18-80 mg, 45-60 mg, 45-80 mg, or 60-80 mg. In certain
preferred embodiments, olokizumab is administered intravenously at
a monthly equivalent dose of 1.8-60 mg. In various embodiments,
olokizumab is administered intravenously at a monthly equivalent
dose of about 1 mg, 1.8 mg, 3.6 mg, 9 mg, 18 mg. 45 mg, 60 mg, or
80 mg. In certain embodiments, olokizumab is administered
intravenously at a monthly equivalent dose of about 1 mg. In
certain embodiments, olokizumab is administered intravenously at a
monthly equivalent dose of about 1.8 mg. In certain embodiments,
olokizumab is administered intravenously at a monthly equivalent
dose of about 3.6 mg. In certain embodiments, olokizumab is
administered intravenously at a monthly equivalent dose of about 9
mg. In certain embodiments, olokizumab is administered
intravenously at a monthly equivalent dose of about 18 mg. In
certain embodiments, olokizumab is administered intravenously at a
monthly equivalent dose of about 45 mg. In certain embodiments,
olokizumab is administered intravenously at a monthly equivalent
dose of about 60 mg. In certain embodiments, olokizumab is
administered intravenously at a monthly equivalent dose of about 80
mg.
[0311] In various embodiments, olokizumab is administered
subcutaneously at a monthly equivalent dose of 1-100 mg, such as
1-3 mg, 1-6 mg, 1-10 mg, 1-15 mg, 1-20 mg, 1-30 mg, 1-50 mg, 1-72
mg, 3-6 mg, 3-10 mg, 3-15 mg, 3-20 mg, 3-30 mg, 3-50 mg, 3-72 mg,
3-100 mg, 6-10 mg, 6-15 mg, 6-20 mg, 6-30 mg, 6-50 mg, 6-72 mg,
6-100 mg, 10-15 mg, 10-20 mg, 10-30 mg, 10-50 mg, 10-72 mg, 10-100
mg, 15-20 mg, 15-30 mg, 15-50 mg, 15-72 mg, 15-100 mg, 20-30 mg,
20-50 mg, 20-72 mg, 20-100 mg, 30-50 mg, 30-72 mg, 30-100 mg, 50-72
mg, 50-100 mg, or 72-100 mg. In certain preferred embodiments,
olokizumab is administered subcutaneously at a monthly equivalent
dose of 3-100 mg. In various embodiments, olokizumab is
administered subcutaneously at a monthly equivalent dose of about 1
mg, 3 mg, 6 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, 72 mg, or 100
mg. In certain embodiments, olokizumab is administered
subcutaneously at a monthly equivalent dose of about 3 mg. In
certain embodiments, olokizumab is administered subcutaneously at a
monthly equivalent dose of about 6 mg. In certain embodiments,
olokizumab is administered subcutaneously at a monthly equivalent
dose of about 15 mg. In certain embodiments, olokizumab is
administered subcutaneously at a monthly equivalent dose of about
30 mg. In certain embodiments, olokizumab is administered
subcutaneously at a monthly equivalent dose of about 72 mg. In
certain embodiments, olokizumab is administered subcutaneously at a
monthly equivalent dose of about 100 mg.
[0312] In some embodiments, the IL-6 antagonist is tocilizumab. In
various embodiments, tocilizumab is administered intravenously at a
monthly equivalent dose of 10-500 mg, such as 10-20 mg, 10-50 mg,
10-100 mg, 10-150 mg, 10-200 mg, 10-250 mg, 10-300 mg, 10 350 mg,
10-400 mg, 20-50 mg, 20-100 mg, 20-150 mg, 20-200 mg, 20-250 mg,
20-300 mg, 20-350 mg, 20-400 mg, 20-500 mg, 50-100 mg, 50-150 mg,
50-200 mg, 50-250 mg, 50-300 mg, 50-350 mg, 50-400 mg, 50-500 mg,
100-150 mg, 100-200 mg, 100-250 mg, 100-300 mg, 100-350 mg, 100-400
mg, 100-500 mg, 150-200 mg, 150-250 mg, 150-300 mg, 150-350 mg,
150-400 mg, 150-500 mg, 200-250 mg, 200-300 mg, 200-350 mg, 200-400
mg, 200-500 mg, 250-300 mg, 250-350 mg, 250-400 mg, 250-500 mg,
300-350 mg, 300-400 mg, 300-500 mg, 350-400 mg, 350-500 mg, or
400-500 mg. In certain preferred embodiments, tocilizumab is
administered intravenously at a monthly equivalent dose of 50-500
mg. In various embodiments, tocilizumab is administered
intravenously at a monthly equivalent dose of about 10 mg, 20 mg,
30 mg, 40 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350
mg, 400 mg, or 500 mg. In certain embodiments, tocilizumab is
administered intravenously at a monthly equivalent dose of about 50
mg. In certain embodiments, tocilizumab is administered
intravenously at a monthly equivalent dose of about 100 mg. In
certain embodiments, tocilizumab is administered intravenously at a
monthly equivalent dose of about 150 mg. In certain embodiments,
tocilizumab is administered intravenously at a monthly equivalent
dose of about 250 mg. In certain embodiments, tocilizumab is
administered intravenously at a monthly equivalent dose of about
350 mg. In certain embodiments, tocilizumab is administered
intravenously at a monthly equivalent dose of about 500 mg.
[0313] In various embodiments, tocilizumab is administered
subcutaneously at a monthly equivalent dose of 50-1000 mg, such
50-80 mg, 50-160 mg, 50-240 mg, 50-400 mg, 50 560 mg, 50-800 mg,
80-160 mg, 80-240 mg, 80-400 mg, 80-560 mg, 80-800 mg, 80 1000 mg,
160-240 mg, 160-400 mg, 160-560, 160-800 mg, 160-1000 mg, 240-400
mg, 240-560 mg, 240-800 mg, 240-1000 mg, 400-560 mg, 400-800 mg,
400-1000 mg, 560-800 mg, 560-1000 mg, or 800-1000 mg. In certain
preferred embodiments, tocilizumab is administered subcutaneously
at a monthly equivalent dose of 80-800 mg. In various embodiments,
tocilizumab is administered subcutaneously at a monthly equivalent
dose of about 50 mg, 80 mg, 160 mg, 240 mg, 400 mg, 560 mg, 800 mg,
or 1000 mg. In certain embodiments, tocilizumab is administered
subcutaneously at a monthly equivalent dose of about 50 mg. In
certain embodiments, tocilizumab is administered subcutaneously at
a monthly equivalent dose of about 80 mg. In certain embodiments,
tocilizumab is administered subcutaneously at a monthly equivalent
dose of about 160 mg. In certain embodiments, tocilizumab is
administered subcutaneously at a monthly equivalent dose of about
240 mg. In certain embodiments, tocilizumab is administered
subcutaneously at a monthly equivalent dose of about 400 mg. In
certain embodiments, tocilizumab is administered subcutaneously at
a monthly equivalent dose of about 560 mg. In certain embodiments,
tocilizumab is administered subcutaneously at a monthly equivalent
dose of about 800 mg. In certain embodiments, tocilizumab is
administered subcutaneously at a monthly equivalent dose of about
1000 mg.
[0314] In some embodiments, the IL-6 antagonist is sarilumab. In
various embodiments, sarilumab is administered intravenously at a
monthly equivalent dose of 10-150 mg, such as 10-12 mg, 10-24 mg,
10-48 mg, 10-60 mg, 10-72 mg, 10-120 mg, 12-24 mg, 12-48 mg, 12-60
mg, 12-72 mg, 12-120 mg, 12-150 mg, 24-48 mg, 24-60 mg, 24-72 mg,
24-120 mg, 24-150 mg, 48-60 mg, 48-72 mg, 48-120 mg, 48-150 mg,
60-72 mg, 60-120 mg, 60-150 mg, 72-120 mg, 72-150 mg, or 120-150
mg. In certain preferred embodiments, sarilumab is administered
intravenously at a monthly equivalent dose of 12-120 mg. In various
embodiments, sarilumab is administered intravenously at a monthly
equivalent dose of 10 mg, 12 mg, 24 mg, 48 mg, 60 mg, 72 mg, 120
mg, or 150 mg. In certain embodiments, sarilumab is administered
intravenously at a monthly equivalent dose of 10 mg. In certain
embodiments, sarilumab is administered intravenously at a monthly
equivalent dose of 12 mg. In certain embodiments, sarilumab is
administered intravenously at a monthly equivalent dose of 24 mg.
In certain embodiments, sarilumab is administered intravenously at
a monthly equivalent dose of 48 mg. In certain embodiments,
sarilumab is administered intravenously at a monthly equivalent
dose of 60 mg. In certain embodiments, sarilumab is administered
intravenously at a monthly equivalent dose of 72 mg. In certain
embodiments, sarilumab is administered intravenously at a monthly
equivalent dose of 120 mg. In certain embodiments, sarilumab is
administered intravenously at a monthly equivalent dose of 150
mg.
[0315] In various embodiments, sarilumab is administered
subcutaneously at a monthly equivalent dose of 10-200 mg, such as
10-20 mg, 10-40 mg, 10-60 mg, 10-80 mg, 10-100 mg, 10-120 mg, 20-40
mg, 20-60 mg, 20-80 mg, 20-100 mg, 20-120 mg, 20-200 mg, 40-60 mg,
40-80 mg, 40-100 mg, 40-120 mg, 40-200 mg, 60-80 mg, 60-100 mg,
60-120 mg, mg, 60-200 mg, 80-100 mg, 80-120 mg, 80-200 mg, 100-120
mg, 100-200 mg, or 120-200 mg. In certain preferred embodiments,
sarilumab is administered subcutaneously at a monthly equivalent
dose of 20-200 mg. In various embodiments, sarilumab is
administered subcutaneously at a monthly equivalent dose of about
10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg,
150 mg, or 200 mg. In certain embodiments, sarilumab is
administered subcutaneously at a monthly equivalent dose of about
20 mg. In certain embodiments, sarilumab is administered
subcutaneously at a monthly equivalent dose of about 40 mg. In
certain embodiments, sarilumab is administered subcutaneously at a
monthly equivalent dose of about 80 mg. In certain embodiments,
sarilumab is administered subcutaneously at a monthly equivalent
dose of about 100 mg. In certain embodiments, sarilumab is
administered subcutaneously at a monthly equivalent dose of about
120 mg. In certain embodiments, sarilumab is administered
subcutaneously at a monthly equivalent dose of about 200 mg.
[0316] In some embodiments, the IL-6 antagonist is vobarilizumab.
In various embodiments, vobarilizumab is administered intravenously
at a monthly equivalent dose of 2-150 mg, such as 2-4 mg, 2-6 mg,
2-30 mg, 2-60 mg, 2-84 mg, 2-120 mg, 4-6 mg, 4-30 mg, 4-60 mg, 4-84
mg, 4-120 mg, 4-150 mg, 6-30 mg, 6-60 mg, 6-84 mg, 6-120 mg, 6-150
mg, 30-60 mg, 30-84 mg, 30-120 mg, 30-150 mg, 60-84 mg, 60-120 mg,
60-150 mg, 84-120 mg, 84-150 mg, or 120-150 mg. In certain
preferred embodiments, vobarilizumab is administered intravenously
at a monthly equivalent dose of 4-120 mg. In various embodiments,
vobarilizumab is administered intravenously at a monthly equivalent
dose of about 2 mg, 4 mg, 6 mg, 30 mg, 60 mg, 84 mg, 120 mg, or 150
mg. In certain embodiments, vobarilizumab is administered
intravenously at a monthly equivalent dose of about 2 mg. In
certain embodiments, vobarilizumab is administered intravenously at
a monthly equivalent dose of about 4 mg. In certain embodiments,
vobarilizumab is administered intravenously at a monthly equivalent
dose of about 6 mg. In certain embodiments, vobarilizumab is
administered intravenously at a monthly equivalent dose of about 30
mg. In certain embodiments, vobarilizumab is administered
intravenously at a monthly equivalent dose of about 60 mg. In
certain embodiments, vobarilizumab is administered intravenously at
a monthly equivalent dose of about 84 mg. In certain embodiments,
vobarilizumab is administered intravenously at a monthly equivalent
dose of about 120 mg. In certain embodiments, vobarilizumab is
administered intravenously at a monthly equivalent dose of about
150 mg.
[0317] In various embodiments, vobarilizumab is administered
subcutaneously at a monthly equivalent dose of 5-200 mg, such as
5-7 mg, 5-10 mg, 5-20 mg, 5-50 mg, 5-70 mg, 5 100 mg, 5-140 mg,
7-10 mg, 7-20 mg, 7-50 mg, 7-70 mg, 7-100 mg, 7-140 mg, 7-200 mg,
10-20 mg, 10-50 mg, 10-70 mg, 10-100 mg, 10-140 mg, 10-200 mg,
20-50 mg, 20-70 mg, 20-100 mg, 20-140 mg, 20-200 mg, 50-70 mg,
50-100 mg, 50-140 mg, 50-200 mg, 70-100 mg, 70-140 mg, 70-200 mg,
100-140 mg, 100-200 mg, or 140-200 mg. In certain preferred
embodiments, vobarilizumab is administered subcutaneously at a
monthly equivalent dose of 7-200 mg. In various embodiments,
vobarilizumab is administered subcutaneously at a monthly
equivalent dose of about 5 mg, 7 mg, 10 mg, 20 mg, 40 mg, 50 mg, 70
mg, 100 mg, 140 mg, or 200 mg. In certain embodiments,
vobarilizumab is administered subcutaneously at a monthly
equivalent dose of about 7 mg. In certain embodiments,
vobarilizumab is administered subcutaneously at a monthly
equivalent dose of about 10 mg. In certain embodiments,
vobarilizumab is administered subcutaneously at a monthly
equivalent dose of about 50 mg. In certain embodiments,
vobarilizumab is administered subcutaneously at a monthly
equivalent dose of about 100 mg. In certain embodiments,
vobarilizumab is administered subcutaneously at a monthly
equivalent dose of about 140 mg. In certain embodiments,
vobarilizumab is administered subcutaneously at a monthly
equivalent dose of about 200 mg.
3. Examples
[0318] The following examples are provided by way of
exemplification and illustration, not limitation.
[0319] 3.1. Example 1: Phase 1/2 Clinical Study
[0320] A Phase 1/2 clinical study was conducted to assess the
safety, pharmacokinetics, and pharmacodynamics of multiple IV doses
of COR-001.
[0321] 3.1.1. Drug Product (COR-001)
[0322] COR-001 is a human IgG1, kappa antibody directed against
interleukin-6 (IL-6). COR-001 contains a "YTE" mutation in its Fc
region. The sequence and other features of COR-001 are described in
Chapter 2.7.1.1 above.
[0323] 3.1.2. Study Design
[0324] The study was a randomized, double-blind, placebo-controlled
trial designed to evaluate the safety, pharmacokinetics, and
pharmacodynamic effects of multiple doses of COR-001 (MEDI5117) or
placebo administered to sequential cohorts of hemodialysis
patients.
[0325] Key inclusion criteria include stage 5 chronic kidney
disease (CKD-5) on hemodialysis, positive for TMPRSS6 736A genotype
(major allele), IL-6 level greater than 4 pg/mL, and erythropoietic
resistive index greater than 8.
[0326] Ten hemodialysis patients were randomized to COR-001 or
placebo within each dosing cohort. When a higher dose than studied
in a prior cohort was initiated, the first 2 (sentinel) patients in
that cohort (randomized 1:1 to COR-001 or placebo) were randomized
first and the remaining patients were randomized at least 48 hours
later, in a 7:1 ratio of COR-001 to placebo. The final ratio of
patients treated with COR-001 vs. placebo were 8:2 in each cohort
of 10 patients. The maximum tolerated dose (MTD) assessment was
based on safety data from Weeks 1 to 3. If more than 2 of 8 active
patients in a cohort experienced a dose-limiting toxicity (DLT),
the MTD was considered to have been exceeded.
[0327] The Dose Escalation Schematic is shown in FIG. 1. COR-001
was administered as an intravenous infusion, started any time
before the last 1 hour of the dialysis treatment. The COR-001 dose
regimens are shown in Table 1 below.
TABLE-US-00008 TABLE 1 Number of Total Cumulative Dose Cohort Dose
Regimen Doses Dose 1 2 mg every 14 days 6 12 mg 2 6 mg every 14
days 6 36 mg 3 6 mg every 14 days 6 36 mg 4 2 mg every 14 days 6 12
mg 5 20 mg every 14 days 6 120 mg 6 20 mg every 14 days 6 120
mg
[0328] The total study duration for an individual patient was
approximately 9 months, excluding the screening period of up to 4
weeks. As shown in FIG. 2, the study included a treatment period of
12 weeks (Week 1 through Week 12), a safety follow-up period of 12
weeks (Week 13 through Week 24), and an extended follow-up period
of 10 weeks (Week 25 through Week 35).
[0329] Interim study-collected data were summarized by treatment
group for the appropriate analysis population, using descriptive
statistics. Descriptive statistics for continuous variables
included number of patients (n), mean, standard deviation (SD),
median, quartiles (Q1 and Q3), minimum (min) and maximum (max)
values. Analysis of categorical variables included frequency and
percentages.
[0330] The changes in high-sensitivity C-reactive protein (hsCRP),
absolute neutrophil count (ANC), lipoprotein(a) level, LDL level,
hemoglobin, transferrin saturation (TSAT), albumin, erythropoietic
resistive index (ERI), handgrip, NT-proBNP, and cardiac MRI were
recorded during the study.
[0331] 3.1.3. Analysis of Clinical Data
[0332] Analyses were performed to determine the effect of COR-001
on C-reactive protein (CRP), the effect of COR-001 on hemoglobin
level, the effect of COR-001 on various cardiac parameters, and the
effect of COR-001 on levels of neutrophils and platelets.
[0333] C-reactive protein (CRP) is a marker of inflammation. CRP
levels increase in response to inflammation, and can be measured
with an hsCRP (high-sensitivity C-reactive protein) test. The hsCRP
level was measured over the course of the treatment period and the
safety follow-up period in patients of the placebo-treated, 2 mg
dose regimen, 6 mg dose regimen, and 20 mg dose regimen groups,
respectively.
[0334] The percentages of patients with post-treatment average
hsCRP <2 mg/L at Week 12 were 44%, 62%, and 85% in the 2 mg dose
regimen, 6 mg dose regimen, and 20 mg dose regimen groups,
respectively, as compared to 14% in the placebo group. The hsCRP
responder analysis shows that COR-001 (anti-IL-6) has a superior
effect on hsCRP than has been reported for canakinumab
(anti-IL1.beta.) in the CANTOS trial. The hsCRP responder rates of
COR-001 in stage 5 chronic kidney disease patients on dialysis at
IV doses of 20 mg and 6 mg (FIG. 3A) were higher than the hsCRP
responder rates of canakinumab at equivalent doses in the CANTOS
trial (FIG. 3B). The in vivo IC50 concentration of COR-001 for CRP
(50% reduction of baseline CRP) is 206 ng/mL.
[0335] COR-001 improved a primary indicator of anemia, hemoglobin
levels. The hemoglobin responder analysis indicated a
dose-dependent hemoglobin responder rate of COR-001 treatment (FIG.
4).
[0336] The effect of COR-001 on various biomarkers of heart failure
was determined. As shown in FIG. 5, COR-001 decreased the level of
the N-terminal prohormone of brain natriuretic peptide (NT-proBNP).
The result indicates that treatment of COR-001 can reduce heart
failure.
[0337] Anti-inflammatory therapies in general, and IL-6 inhibitory
therapies in particular, create a risk of inducing immune
suppression, thereby promoting the emergence of infections,
sometimes serious in nature. Immune suppression can be measured by
neutrophil counts. The effect of COR-001 on neutrophil counts was
determined.
[0338] Surprisingly, despite significant reduction in inflammation,
as measured by hsCRP levels (FIG. 3A), the absolute neutrophil
count of patients treated with COR-001 did not decline to below
normal levels. No opportunistic infections were observed during the
treatment. As shown in FIG. 6A, the percentages of patients with
absolute neutrophil count below 2.0.times.10.sup.9/L were not
increased with COR-001 at all tested doses as compared to the
placebo group. All patients treated with COR-001 at all tested
doses had an absolute neutrophil count above 1.5.times.10.sup.9/L.
The in vivo IC50 concentration of COR-001 for neutrophil count (50%
reduction of baseline neutrophil count) is 5540 ng/mL.
[0339] The percentages of patients with platelet count below
100.times.10.sup.9/L were less than 30% with COR-001 for all tested
doses (FIG. 6B). The in vivo IC50 concentration of COR-001 for
platelet count (50% reduction of baseline platelet count) is 13800
ng/mL.
[0340] In summary, the clinical data indicate that COR-001
treatment at doses of 2 mg, 6 mg, and 20 mg can reduce inflammation
without inducing immune suppression in patients with stage 5
chronic kidney disease (CKD-5) on dialysis, whereas the absolute
neutrophil count was not decreased significantly in patients
treated with COR-001.
[0341] Administration of COR-001 reduced CRP in a dose-dependent
matter. In addition, COR-001 increased hemoglobin level in these
patients. COR-001 decreased the biomarkers of heart failure
NT-proBNP.
4. Incorporation by Reference
[0342] All publications, patents, patent applications and other
documents cited in this application are hereby incorporated by
reference in their entireties for all purposes to the same extent
as if each individual publication, patent, patent application or
other document were individually indicated to be incorporated by
reference for all purposes.
5. Equivalents
[0343] While various specific embodiments have been illustrated and
described, the above specification is not restrictive. It will be
appreciated that various changes can be made without departing from
the spirit and scope of the invention(s). Many variations will
become apparent to those skilled in the art upon review of this
specification.
Sequence CWU 1
1
141277PRTHomo sapiens 1Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly
Pro Cys Ala Ala Leu1 5 10 15Leu Leu Leu Gly Leu Gly Leu Ser Thr Val
Thr Gly Leu His Cys Val 20 25 30Gly Asp Thr Tyr Pro Ser Asn Asp Arg
Cys Cys His Glu Cys Arg Pro 35 40 45Gly Asn Gly Met Val Ser Arg Cys
Ser Arg Ser Gln Asn Thr Val Cys 50 55 60Arg Pro Cys Gly Pro Gly Phe
Tyr Asn Asp Val Val Ser Ser Lys Pro65 70 75 80Cys Lys Pro Cys Thr
Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys 85 90 95Gln Leu Cys Thr
Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly 100 105 110Thr Gln
Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys 115 120
125Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala
Ser Asn145 150 155 160Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro
Pro Ala Thr Gln Pro 165 170 175Gln Glu Thr Gln Gly Pro Pro Ala Arg
Pro Ile Thr Val Gln Pro Thr 180 185 190Glu Ala Trp Pro Arg Thr Ser
Gln Gly Pro Ser Thr Arg Pro Val Glu 195 200 205Val Pro Gly Gly Arg
Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val 210 215 220Leu Gly Leu
Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu225 230 235
240Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
245 250 255Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala
His Ser 260 265 270Thr Leu Ala Lys Ile 27521201DNAHomo sapiens
2aatattagag tctcaacccc caataaatat aggactggag atgtctgagg ctcattctgc
60cctcgagccc accgggaacg aaagagaagc tctatctccc ctccaggagc ccagctatga
120actccttctc cacaagcgcc ttcggtccag ttgccttctc cctggggctg
ctcctggtgt 180tgcctgctgc cttccctgcc ccagtacccc caggagaaga
ttccaaagat gtagccgccc 240cacacagaca gccactcacc tcttcagaac
gaattgacaa acaaattcgg tacatcctcg 300acggcatctc agccctgaga
aaggagacat gtaacaagag taacatgtgt gaaagcagca 360aagaggcact
ggcagaaaac aacctgaacc ttccaaagat ggctgaaaaa gatggatgct
420tccaatctgg attcaatgag gagacttgcc tggtgaaaat catcactggt
cttttggagt 480ttgaggtata cctagagtac ctccagaaca gatttgagag
tagtgaggaa caagccagag 540ctgtgcagat gagtacaaaa gtcctgatcc
agttcctgca gaaaaaggca aagaatctag 600atgcaataac cacccctgac
ccaaccacaa atgccagcct gctgacgaag ctgcaggcac 660agaaccagtg
gctgcaggac atgacaactc atctcattct gcgcagcttt aaggagttcc
720tgcagtccag cctgagggct cttcggcaaa tgtagcatgg gcacctcaga
ttgttgttgt 780taatgggcat tccttcttct ggtcagaaac ctgtccactg
ggcacagaac ttatgttgtt 840ctctatggag aactaaaagt atgagcgtta
ggacactatt ttaattattt ttaatttatt 900aatatttaaa tatgtgaagc
tgagttaatt tatgtaagtc atatttatat ttttaagaag 960taccacttga
aacattttat gtattagttt tgaaataata atggaaagtg gctatgcagt
1020ttgaatatcc tttgtttcag agccagatca tttcttggaa agtgtaggct
tacctcaaat 1080aaatggctaa cttatacata tttttaaaga aatatttata
ttgtatttat ataatgtata 1140aatggttttt ataccaataa atggcatttt
aaaaaattca gcaaaaaaaa aaaaaaaaaa 1200a 12013468PRTHomo sapiens 3Met
Leu Ala Val Gly Cys Ala Leu Leu Ala Ala Leu Leu Ala Ala Pro1 5 10
15Gly Ala Ala Leu Ala Pro Arg Arg Cys Pro Ala Gln Glu Val Ala Arg
20 25 30Gly Val Leu Thr Ser Leu Pro Gly Asp Ser Val Thr Leu Thr Cys
Pro 35 40 45Gly Val Glu Pro Glu Asp Asn Ala Thr Val His Trp Val Leu
Arg Lys 50 55 60Pro Ala Ala Gly Ser His Pro Ser Arg Trp Ala Gly Met
Gly Arg Arg65 70 75 80Leu Leu Leu Arg Ser Val Gln Leu His Asp Ser
Gly Asn Tyr Ser Cys 85 90 95Tyr Arg Ala Gly Arg Pro Ala Gly Thr Val
His Leu Leu Val Asp Val 100 105 110Pro Pro Glu Glu Pro Gln Leu Ser
Cys Phe Arg Lys Ser Pro Leu Ser 115 120 125Asn Val Val Cys Glu Trp
Gly Pro Arg Ser Thr Pro Ser Leu Thr Thr 130 135 140Lys Ala Val Leu
Leu Val Arg Lys Phe Gln Asn Ser Pro Ala Glu Asp145 150 155 160Phe
Gln Glu Pro Cys Gln Tyr Ser Gln Glu Ser Gln Lys Phe Ser Cys 165 170
175Gln Leu Ala Val Pro Glu Gly Asp Ser Ser Phe Tyr Ile Val Ser Met
180 185 190Cys Val Ala Ser Ser Val Gly Ser Lys Phe Ser Lys Thr Gln
Thr Phe 195 200 205Gln Gly Cys Gly Ile Leu Gln Pro Asp Pro Pro Ala
Asn Ile Thr Val 210 215 220Thr Ala Val Ala Arg Asn Pro Arg Trp Leu
Ser Val Thr Trp Gln Asp225 230 235 240Pro His Ser Trp Asn Ser Ser
Phe Tyr Arg Leu Arg Phe Glu Leu Arg 245 250 255Tyr Arg Ala Glu Arg
Ser Lys Thr Phe Thr Thr Trp Met Val Lys Asp 260 265 270Leu Gln His
His Cys Val Ile His Asp Ala Trp Ser Gly Leu Arg His 275 280 285Val
Val Gln Leu Arg Ala Gln Glu Glu Phe Gly Gln Gly Glu Trp Ser 290 295
300Glu Trp Ser Pro Glu Ala Met Gly Thr Pro Trp Thr Glu Ser Arg
Ser305 310 315 320Pro Pro Ala Glu Asn Glu Val Ser Thr Pro Met Gln
Ala Leu Thr Thr 325 330 335Asn Lys Asp Asp Asp Asn Ile Leu Phe Arg
Asp Ser Ala Asn Ala Thr 340 345 350Ser Leu Pro Val Gln Asp Ser Ser
Ser Val Pro Leu Pro Thr Phe Leu 355 360 365Val Ala Gly Gly Ser Leu
Ala Phe Gly Thr Leu Leu Cys Ile Ala Ile 370 375 380Val Leu Arg Phe
Lys Lys Thr Trp Lys Leu Arg Ala Leu Lys Glu Gly385 390 395 400Lys
Thr Ser Met His Pro Pro Tyr Ser Leu Gly Gln Leu Val Pro Glu 405 410
415Arg Pro Arg Pro Thr Pro Val Leu Val Pro Leu Ile Ser Pro Pro Val
420 425 430Ser Pro Ser Ser Leu Gly Ser Asp Asn Thr Ser Ser His Asn
Arg Pro 435 440 445Asp Ala Arg Asp Pro Arg Ser Pro Tyr Asp Ile Ser
Asn Thr Asp Tyr 450 455 460Phe Phe Pro Arg4654918PRTHomo sapiens
4Met Leu Thr Leu Gln Thr Trp Leu Val Gln Ala Leu Phe Ile Phe Leu1 5
10 15Thr Thr Glu Ser Thr Gly Glu Leu Leu Asp Pro Cys Gly Tyr Ile
Ser 20 25 30Pro Glu Ser Pro Val Val Gln Leu His Ser Asn Phe Thr Ala
Val Cys 35 40 45Val Leu Lys Glu Lys Cys Met Asp Tyr Phe His Val Asn
Ala Asn Tyr 50 55 60Ile Val Trp Lys Thr Asn His Phe Thr Ile Pro Lys
Glu Gln Tyr Thr65 70 75 80Ile Ile Asn Arg Thr Ala Ser Ser Val Thr
Phe Thr Asp Ile Ala Ser 85 90 95Leu Asn Ile Gln Leu Thr Cys Asn Ile
Leu Thr Phe Gly Gln Leu Glu 100 105 110Gln Asn Val Tyr Gly Ile Thr
Ile Ile Ser Gly Leu Pro Pro Glu Lys 115 120 125Pro Lys Asn Leu Ser
Cys Ile Val Asn Glu Gly Lys Lys Met Arg Cys 130 135 140Glu Trp Asp
Gly Gly Arg Glu Thr His Leu Glu Thr Asn Phe Thr Leu145 150 155
160Lys Ser Glu Trp Ala Thr His Lys Phe Ala Asp Cys Lys Ala Lys Arg
165 170 175Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr Ser Thr Val Tyr
Phe Val 180 185 190Asn Ile Glu Val Trp Val Glu Ala Glu Asn Ala Leu
Gly Lys Val Thr 195 200 205Ser Asp His Ile Asn Phe Asp Pro Val Tyr
Lys Val Lys Pro Asn Pro 210 215 220Pro His Asn Leu Ser Val Ile Asn
Ser Glu Glu Leu Ser Ser Ile Leu225 230 235 240Lys Leu Thr Trp Thr
Asn Pro Ser Ile Lys Ser Val Ile Ile Leu Lys 245 250 255Tyr Asn Ile
Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile 260 265 270Pro
Pro Glu Asp Thr Ala Ser Thr Arg Ser Ser Phe Thr Val Gln Asp 275 280
285Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Cys Met Lys Glu
290 295 300Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser
Gly Ile305 310 315 320Thr Tyr Glu Asp Arg Pro Ser Lys Ala Pro Ser
Phe Trp Tyr Lys Ile 325 330 335Asp Pro Ser His Thr Gln Gly Tyr Arg
Thr Val Gln Leu Val Trp Lys 340 345 350Thr Leu Pro Pro Phe Glu Ala
Asn Gly Lys Ile Leu Asp Tyr Glu Val 355 360 365Thr Leu Thr Arg Trp
Lys Ser His Leu Gln Asn Tyr Thr Val Asn Ala 370 375 380Thr Lys Leu
Thr Val Asn Leu Thr Asn Asp Arg Tyr Leu Ala Thr Leu385 390 395
400Thr Val Arg Asn Leu Val Gly Lys Ser Asp Ala Ala Val Leu Thr Ile
405 410 415Pro Ala Cys Asp Phe Gln Ala Thr His Pro Val Met Asp Leu
Lys Ala 420 425 430Phe Pro Lys Asp Asn Met Leu Trp Val Glu Trp Thr
Thr Pro Arg Glu 435 440 445Ser Val Lys Lys Tyr Ile Leu Glu Trp Cys
Val Leu Ser Asp Lys Ala 450 455 460Pro Cys Ile Thr Asp Trp Gln Gln
Glu Asp Gly Thr Val His Arg Thr465 470 475 480Tyr Leu Arg Gly Asn
Leu Ala Glu Ser Lys Cys Tyr Leu Ile Thr Val 485 490 495Thr Pro Val
Tyr Ala Asp Gly Pro Gly Ser Pro Glu Ser Ile Lys Ala 500 505 510Tyr
Leu Lys Gln Ala Pro Pro Ser Lys Gly Pro Thr Val Arg Thr Lys 515 520
525Lys Val Gly Lys Asn Glu Ala Val Leu Glu Trp Asp Gln Leu Pro Val
530 535 540Asp Val Gln Asn Gly Phe Ile Arg Asn Tyr Thr Ile Phe Tyr
Arg Thr545 550 555 560Ile Ile Gly Asn Glu Thr Ala Val Asn Val Asp
Ser Ser His Thr Glu 565 570 575Tyr Thr Leu Ser Ser Leu Thr Ser Asp
Thr Leu Tyr Met Val Arg Met 580 585 590Ala Ala Tyr Thr Asp Glu Gly
Gly Lys Asp Gly Pro Glu Phe Thr Phe 595 600 605Thr Thr Pro Lys Phe
Ala Gln Gly Glu Ile Glu Ala Ile Val Val Pro 610 615 620Val Cys Leu
Ala Phe Leu Leu Thr Thr Leu Leu Gly Val Leu Phe Cys625 630 635
640Phe Asn Lys Arg Asp Leu Ile Lys Lys His Ile Trp Pro Asn Val Pro
645 650 655Asp Pro Ser Lys Ser His Ile Ala Gln Trp Ser Pro His Thr
Pro Pro 660 665 670Arg His Asn Phe Asn Ser Lys Asp Gln Met Tyr Ser
Asp Gly Asn Phe 675 680 685Thr Asp Val Ser Val Val Glu Ile Glu Ala
Asn Asp Lys Lys Pro Phe 690 695 700Pro Glu Asp Leu Lys Ser Leu Asp
Leu Phe Lys Lys Glu Lys Ile Asn705 710 715 720Thr Glu Gly His Ser
Ser Gly Ile Gly Gly Ser Ser Cys Met Ser Ser 725 730 735Ser Arg Pro
Ser Ile Ser Ser Ser Asp Glu Asn Glu Ser Ser Gln Asn 740 745 750Thr
Ser Ser Thr Val Gln Tyr Ser Thr Val Val His Ser Gly Tyr Arg 755 760
765His Gln Val Pro Ser Val Gln Val Phe Ser Arg Ser Glu Ser Thr Gln
770 775 780Pro Leu Leu Asp Ser Glu Glu Arg Pro Glu Asp Leu Gln Leu
Val Asp785 790 795 800His Val Asp Gly Gly Asp Gly Ile Leu Pro Arg
Gln Gln Tyr Phe Lys 805 810 815Gln Asn Cys Ser Gln His Glu Ser Ser
Pro Asp Ile Ser His Phe Glu 820 825 830Arg Ser Lys Gln Val Ser Ser
Val Asn Glu Glu Asp Phe Val Arg Leu 835 840 845Lys Gln Gln Ile Ser
Asp His Ile Ser Gln Ser Cys Gly Ser Gly Gln 850 855 860Met Lys Met
Phe Gln Glu Val Ser Ala Ala Asp Ala Phe Gly Pro Gly865 870 875
880Thr Glu Gly Gln Val Glu Arg Phe Glu Thr Val Gly Met Glu Ala Ala
885 890 895Thr Asp Glu Gly Met Pro Lys Ser Tyr Leu Pro Gln Thr Val
Arg Gln 900 905 910Gly Gly Tyr Met Pro Gln 9155224PRTHomo sapiens
5Met Glu Lys Leu Leu Cys Phe Leu Val Leu Thr Ser Leu Ser His Ala1 5
10 15Phe Gly Gln Thr Asp Met Ser Arg Lys Ala Phe Val Phe Pro Lys
Glu 20 25 30Ser Asp Thr Ser Tyr Val Ser Leu Lys Ala Pro Leu Thr Lys
Pro Leu 35 40 45Lys Ala Phe Thr Val Cys Leu His Phe Tyr Thr Glu Leu
Ser Ser Thr 50 55 60Arg Gly Tyr Ser Ile Phe Ser Tyr Ala Thr Lys Arg
Gln Asp Asn Glu65 70 75 80Ile Leu Ile Phe Trp Ser Lys Asp Ile Gly
Tyr Ser Phe Thr Val Gly 85 90 95Gly Ser Glu Ile Leu Phe Glu Val Pro
Glu Val Thr Val Ala Pro Val 100 105 110His Ile Cys Thr Ser Trp Glu
Ser Ala Ser Gly Ile Val Glu Phe Trp 115 120 125Val Asp Gly Lys Pro
Arg Val Arg Lys Ser Leu Lys Lys Gly Tyr Thr 130 135 140Val Gly Ala
Glu Ala Ser Ile Ile Leu Gly Gln Glu Gln Asp Ser Phe145 150 155
160Gly Gly Asn Phe Glu Gly Ser Gln Ser Leu Val Gly Asp Ile Gly Asn
165 170 175Val Asn Met Trp Asp Phe Val Leu Ser Pro Asp Glu Ile Asn
Thr Ile 180 185 190Tyr Leu Gly Gly Pro Phe Ser Pro Asn Val Leu Asn
Trp Arg Ala Leu 195 200 205Lys Tyr Glu Val Gln Gly Glu Val Phe Thr
Lys Pro Gln Leu Trp Pro 210 215 220684PRTHomo sapiens 6Met Ala Leu
Ser Ser Gln Ile Trp Ala Ala Cys Leu Leu Leu Leu Leu1 5 10 15Leu Leu
Ala Ser Leu Thr Ser Gly Ser Val Phe Pro Gln Gln Thr Gly 20 25 30Gln
Leu Ala Glu Leu Gln Pro Gln Asp Arg Ala Gly Ala Arg Ala Ser 35 40
45Trp Met Pro Met Phe Gln Arg Arg Arg Arg Arg Asp Thr His Phe Pro
50 55 60Ile Cys Ile Phe Cys Cys Gly Cys Cys His Arg Ser Lys Cys Gly
Met65 70 75 80Cys Cys Lys Thr75PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 7Ser Asn Tyr Met Ile1
5817PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 8Asp Leu Tyr Tyr Tyr Ala Gly Asp Thr Tyr Tyr Ala
Asp Ser Val Lys1 5 10 15Gly911PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 9Trp Ala Asp Asp His Pro Pro
Trp Ile Asp Leu1 5 101011PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 10Arg Ala Ser Gln Gly Ile Ser
Ser Trp Leu Ala1 5 10117PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 11Lys Ala Ser Thr Leu Glu
Ser1 5128PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 12Gln Gln Ser Trp Leu Gly Gly Ser1
513450PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 13Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
Phe Thr Ile Ser Ser Asn 20 25 30Tyr Met Ile Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Asp Leu Tyr Tyr Tyr Ala Gly
Asp Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Met Ser
Arg Asp Ile Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Trp Ala
Asp Asp His Pro Pro Trp Ile Asp Leu Trp Gly Arg 100 105 110Gly Thr
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120
125Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140Leu Gly Cys Leu Val Lys Asp
Tyr Phe Pro Glu Pro Val Thr Val Ser145 150 155 160Trp Asn Ser Gly
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175Leu Gln
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185
190Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
Cys Asp 210 215 220Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
Leu Leu Gly Gly225 230 235 240Pro Ser Val Phe Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu Tyr Ile 245 250 255Thr Arg Glu Pro Glu Val Thr
Cys Val Val Val Asp Val Ser His Glu 260 265 270Asp Pro Glu Val Lys
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285Asn Ala Lys
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300Val
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys305 310
315 320Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
Glu 325 330 335Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr 340 345 350Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
Asn Gln Val Ser Leu 355 360 365Thr Cys Leu Val Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp 370 375 380Glu Ser Asn Gly Gln Pro Glu
Asn Asn Tyr Lys Thr Thr Pro Pro Val385 390 395 400Leu Asp Ser Asp
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415Lys Ser
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425
430Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445Gly Lys 45014213PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 14Asp Ile Gln Met Thr Gln
Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45Tyr Lys Ala
Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75
80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Trp Leu Gly Gly Ser
85 90 95Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu
Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200
205Asn Arg Gly Glu Cys 210
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