U.S. patent application number 16/983998 was filed with the patent office on 2020-11-19 for methods of treating antibody-mediated rejection in organ transplant patients with c1-esterase inhibitor.
The applicant listed for this patent is Shire ViroPharma Incorporated. Invention is credited to Colin Broom, Marc E. Uknis.
Application Number | 20200360495 16/983998 |
Document ID | / |
Family ID | 1000004993631 |
Filed Date | 2020-11-19 |
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United States Patent
Application |
20200360495 |
Kind Code |
A1 |
Broom; Colin ; et
al. |
November 19, 2020 |
METHODS OF TREATING ANTIBODY-MEDIATED REJECTION IN ORGAN TRANSPLANT
PATIENTS WITH C1-ESTERASE INHIBITOR
Abstract
A method and composition for treating or preventing
antibody-mediated rejection (AMR) of a transplanted organ are
provided.
Inventors: |
Broom; Colin; (Devon,
PA) ; Uknis; Marc E.; (Chadds Ford, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Shire ViroPharma Incorporated |
Lexington |
MA |
US |
|
|
Family ID: |
1000004993631 |
Appl. No.: |
16/983998 |
Filed: |
August 3, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15844850 |
Dec 18, 2017 |
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16983998 |
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14550075 |
Nov 21, 2014 |
9895428 |
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15844850 |
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62029086 |
Jul 25, 2014 |
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61907550 |
Nov 22, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 38/55 20130101;
C07K 16/00 20130101; A61K 38/57 20130101; A61K 45/06 20130101; A61K
2035/122 20130101; A61K 2039/505 20130101; A61K 35/16 20130101 |
International
Class: |
A61K 38/57 20060101
A61K038/57; A61K 38/55 20060101 A61K038/55; A61K 35/16 20060101
A61K035/16; C07K 16/00 20060101 C07K016/00; A61K 45/06 20060101
A61K045/06 |
Claims
1. A C1 esterase inhibitor (C1-INH) for use in a method of treating
antibody-mediated rejection (AMR) of an organ allograft in a
patient in need thereof.
2. A C1-INH for use according to claim 1, wherein the method
comprises early and/or short term duration administration of the
inhibitor.
3. A C1-INH for use according to claim 1 or 2 wherein the method
comprises administration of the inhibitor in an amount sufficient
to provide long-lasting therapeutic effect.
4. A C1-INH for use according to any preceding claim, wherein the
patient has been subjected to plasmapheresis or is currently
subject to plasmapheresis.
5. A C1-INH for use according to any preceding claim wherein the
method further comprises subjecting the patient to
plasmapheresis.
6. A C1-INH for use according to any preceding claim, wherein the
method further comprises administering fresh frozen plasma.
7. A C1-INH for use according to any preceding claim, wherein the
method further comprises administering intravenous
immunoglobulin.
8. A C1-INH for use according to any preceding claim, wherein the
method further comprises administering an anti-lymphocyte
preparation, rituximab, bortezomib, eculizumab, or a combination
thereof.
9. A C1-INH for use according to any preceding claim, wherein the
organ is a solid organ.
10. A C1-INH for use according to claim 9, wherein the solid organ
is selected from the group consisting of kidney, pancreas,
intestine, heart, lung, liver, and a combination thereof.
11. A C1-INH for use according to any one of the preceding claims,
wherein the organ is a kidney.
12. A C1-INH for use according to claim 11, wherein the method
further comprises administering intravenous immunoglobulin and said
patient has been subjected to plasmapheresis or is currently
subject to plasmapheresis.
13. A C1-INH and an additional biologically active agent selected
from the group consisting of an anti-lymphocyte preparation,
rituximab, bortezomib, eculizumab, immunoglobulin (Ig), and a
combination thereof as a combined preparation for concurrent or
sequential use in a method of treatment of antibody-mediated
rejection (AMR) of an organ allograft in a patient in need
thereof.
14. The C1-INH and an additional biologically active agent for use
according to claim 13, wherein the additional biologically active
agent is immunoglobulin, preferably intravenous immunoglobulin.
15. The C1-INH and an additional biologically active agent for use
according to claim 13 or 14 wherein the organ is as defined in any
one of claims 9 to 11, preferably a kidney.
16. The C1-INH and an additional biologically active agent for use
according to any one of claims 13 to 15, wherein said patient has
been subjected to plasmapheresis or is currently subject to
plasmapheresis.
17. The C1-INH and an additional biologically active agent for use
according to any one of claims 13 to 16 said method further
comprising subjecting the patient to plasmapheresis.
18. The C1-INH and an additional biologically active agent for use
according to any one of claims 13 to 15, wherein the wherein the
organ is a kidney, the additional biologically active agent is
intravenous immunoglobulin and said patient has been subjected to
plasmapheresis or is currently subject to plasmapheresis.
19. A kit comprising: (i) C1-INH; and (ii) an additional
biologically active agent selected from the group consisting of an
anti-lymphocyte preparation, rituximab, bortezomib, eculizumab,
immunoglobulin (Ig), and a combination thereof, wherein said
components (i) and (ii) are packaged for concurrent or sequential
administration to a patient, optionally for use in a method of
treatment of antibody-mediated rejection (AMR) of an organ
allograft in the patient.
20. The kit of claim 19, wherein the method further comprises
subjecting the patient to plasmapheresis.
21. A method of treating antibody-mediated rejection (AMR) of an
organ allograft in a patient in need thereof, the method comprising
early and/or short term duration administration of a
therapeutically effective amount of a C1 esterase inhibitor
(C1-INH), wherein the therapeutically effective amount of the
C1-INH is sufficient to provide long-lasting therapeutic
effect.
22. The method of claim 21, further comprising subjecting the
patient to plasmapheresis.
23. The method according to claim 21 or 22, further comprising
administering fresh frozen plasma.
24. The method according to any one of claims 21 to 23, further
comprising administering intravenous immunoglobulin.
25. The method according to any one of claims 21 to 24, further
comprising administering an anti-lymphocyte preparation, rituximab,
bortezomib, eculizumab, or a combination thereof.
26. The method according to any one of claims 21 to 25, wherein the
organ is a solid organ.
27. The method according to claim 26, wherein the solid organ is
selected from the group consisting of kidney, pancreas, intestine,
heart, lung, liver, and a combination thereof.
28. The method according to any one of claims 21 to 27, wherein the
organ is a kidney.
29. A pharmaceutical composition comprising a C1-esterase inhibitor
(C1-INH); an additional biologically active agent; and a
pharmaceutically acceptable carrier medium.
30. The pharmaceutical composition of claim 29, wherein the
biologically active agent is selected from the group consisting of
an anti-lymphocyte preparation, rituximab, bortezomib, eculizumab,
immunoglobulin (Ig), and a combination thereof.
31. A method of treating antibody-mediated rejection (AMR) in a
patient receiving or who has received a kidney transplant, the
method comprising administering sufficient therapeutic amounts of
intravenous immunoglobulin and a C1-INH inhibitor to a patient who
has or is currently subject to plasmapheresis
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/907,550, filed Nov. 22, 2013, and U.S.
Provisional Application No. 62/029,086, filed Jul. 25, 2014, the
entirety of which are incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The present invention relates generally to methods and
compositions for treating organ transplant rejection in patients
and more particularly but not exclusively to methods and
pharmaceutical compositions for treating or preventing
antibody-mediated rejection in organ transplant patients using a
C1-esterase inhibitor.
BACKGROUND OF THE INVENTION
[0003] Each year patients are prohibited from receiving a
potentially life-saving organ transplant because of a pre-existing
antibody directed against the donor's cell surface human leukocyte
antigens (HLA). Such patients are considered "sensitized" to their
donor organ, which may be the result of previous transplantations,
pregnancy, and/or blood transfusions. The presence of certain
donor-specific antibodies (DSA) is a contraindication to
transplantation regardless of other factors that may indicate a
donor match. DSA presence may cause hyperacute (immediate)
antibody-mediated rejection (AMR) of the donor organ
post-transplantation and possible loss of the donated organ.
Patients having DSA (i.e., sensitized patients) thus spend a
significantly longer time waiting for an acceptable donor organ.
Thus, sensitized patients face not one, but at least two hurdles to
organ donation: (1) blood type compatibility, and (2)
sensitization. Furthermore, some patients may develop antibodies to
their donor organ after transplantation, and such DSA is termed "de
novo." It is now known that a majority of patients that lose their
transplant to chronic rejection do so as a result of de novo
DSA.
[0004] At present, there are few treatment options available to
sensitized patients with antibody mediated rejection. The
treatments available include, for example, rituximab, and
plasmapheresis with, or without, intravenous immunoglobulin
(IVIg).
[0005] Although the treatments available show varying effectiveness
for treating AMR initially, their effects become diminished and are
not sustained in nearly half of patients. Thus, the long term
effect of currently available treatments is poor and an enormous
unmet need exists in the field for efficacious treatments of AMR
and treatments and compositions that improve overall transplant
survival for patients receiving cross-match positive organ
transplants.
SUMMARY OF THE INVENTION
[0006] The present invention meets the needs in the field by
providing methods and compositions for advantageously administering
a C1-esterase inhibitor (C1-INH) protein to organ transplant
patients who experience or are at risk of experiencing
antibody-mediated rejection (AMR) of the transplanted organ.
[0007] In one aspect, the invention provides a method of treating
AMR of an organ allograft in a patient in need thereof. The method
includes early and/or short term duration administration of a
therapeutically effective amount of a C1-INH, wherein the
therapeutically effective amount of the C1-INH is sufficient to
provide long-lasting therapeutic effect. The C1-INH may be a human
plasma derived C1-INH, such as Cinryze.RTM.. Optionally, the method
of the invention may include subjecting the patient to
plasmapheresis for removing DSA. Early, short term treatment with
C1-INH, which may be an adjunct to plasmapheresis, can reduce the
rate of chronic organ allograft rejection compared to
plasmapheresis alone.
[0008] In other embodiments, the method of the invention may
comprise administering intravenous immunoglobulin (IV Ig) and/or
fresh frozen plasma. In a further embodiment, the method of the
invention may comprise administering an anti-lymphocyte
preparation, rituximab, eculizumab, bortezomib, or a combination
thereof. In certain embodiments of the method of the invention, the
patient is being or has been treated with other known therapies for
treating hyper-acute and/or acute AMR.
[0009] Additionally, in the method of the invention the organ to be
treated may be a solid organ. Moreover, the solid organ may be
selected from the group consisting of kidney, pancreas, intestine,
heart, lung, and liver. In certain embodiments, the organ is
kidney.
[0010] In another aspect, the invention provides a pharmaceutical
composition for treating or delaying the progression of AMR of an
organ allograft in a patient in need thereof. The pharmaceutical
composition may include a C1-INH; an additional biologically active
agent, such as an anti-lymphocyte preparation, rituximab,
eculizumab, immunoglobulin (Ig), and combinations thereof; and a
pharmaceutically acceptable carrier medium.
[0011] In contrast to the treatments currently available in the
art, the invention provides an efficacious early and/or short term
duration therapy for treating AMR in transplant recipients, as well
as patients awaiting or undergoing organ transplantation, that
provides long-lasting therapeutic effect.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The foregoing summary and the following detailed description
of the exemplary embodiments of the present invention may be
further understood when read in conjunction with the appended
drawings, in which:
[0013] FIG. 1 schematically illustrates the effects of a
C1-esterase inhibitor (C1-INH) on the coagulation, contact, and
complement systems. As referred to therein: kallikrein (KK); high
molecular weight kininogen (HMWK); mannose-binding protein (MBP);
MBP-associated serine protease (MASP); tissue plasminogen activator
(tPA); and fibrin degradation product (FDP).
[0014] FIG. 2 diagrammatically illustrates an exemplary design for
C1-INH inhibitor dosing using Cinryze.RTM. as the C1-INH. As
referred to therein: (a) biopsy-proven AMR within 12 months after
transplant; (b) first dose of either Cinryze.RTM. or placebo within
72 hours after qualifying biopsy; (c) day 20 (.+-.24 hours) after
first dose of either Cinryze.RTM. or placebo; and (d) day 90
(.+-.24 hours) after first dose of either Cinryze.RTM. or
placebo.
[0015] FIG. 3 is a table indicating the standards of care provided
to subjects in an exemplary study following the course in FIG. 2
where, of 14 subjects, 7 where treated with placebo and 7 were
treated with a C1-INH. As referred to therein: fresh frozen plasma
(FFP) and packed red blood cell transfusion (PRBC).
[0016] FIGS. 4A and 4B are graphs illustrating functional C1-INH
plasma concentration levels (cohort means) in treated patients
after infusion with either Cinryze.RTM. or placebo. FIG. 4A
graphically demonstrates the mean plasma concentration of
functional C1-INH after infusion with either Cinryze.RTM. or
placebo over the course of 13 days in the exemplary study. FIG. 4B
graphically demonstrates the mean plasma concentration of
functional C1-INH after infusion with either Cinryze.RTM. or
placebo on day 13 of the exemplary study. Both FIGS. 4A and 4B are
corrected means for each cohort, such that baseline levels of
C1-INH functional were subtracted.
[0017] FIG. 5 graphically represents the mean change in renal
function (i.e., creatinine clearance) in patients treated with
either Cinryze.RTM. or placebo. Creatinine clearance is greatly
reduced in AMR patients. By administering Cinryze.RTM., as compared
to placebo, the creatinine clearance is stabilized after
approximately 7 days and does not drop off to the same degree as
those patients treated with placebo. However, it is noted that the
patients in the exemplary study are treated with plasmapheresis
(and/or IVIg) and either Cinryze.RTM. or placebo.
[0018] FIGS. 6A and 6B display renal tissue slices stained with
hematoxylin and eosin (H&E) stain that illustrate and contrast
the presence of chronic glomerulopathy (CG). FIG. 6A indicates a
normal renal tissue slice at 6 months post-transplant in a patient
treated with Cinryze.RTM. that is not displaying CG (one of the 6/7
patients). FIG. 6B indicates a renal tissue slice at 6 months
post-transplant that indicates CG in a patient treated with placebo
(one of the 3/7 patients).
[0019] FIGS. 7A and 7B provide electron microscopy (EM) images of
peritubual capillaries (PTC). FIG. 7A represents an exemplary
normal EM image of a PTC. FIG. 7B represents an EM image of a PTC
obtained at 6 months post-transplant demonstrating glomerulopathy
an patient treated with placebo (one of the 3/7 patients). In FIG.
7A, CL=capillary lumen, E=epithelium, and BS=basement membrane.
[0020] FIG. 8 includes tables of measured C1-INH antigen and
functional C1-INH levels in subjects at day 13 of an exemplary
study where the subjects were treated with either placebo or C1-INH
in addition to the standard of care (plasmapheresis and/or IVIg).
The C1-INH antigen levels reported are based on a measurement of
protein weight concentration with conversion to U/mL using the
conversion factor of 0.067 U/ml=1 mg/1 dL.
[0021] FIGS. 9A to 9H graphically correlate the levels of C1-INH
antigen and functional C1-INH measured in patients at day 13 of the
exemplary study (FIG. 8) with respect to their 6 month clinical
outcome. As used therein: CG indicates those patients that had poor
outcomes (e.g., 3/7 patients in placebo cohort, 1/7 patients in
Cinryze.RTM. cohort); Antigen (AG); and functional (Fnct).
Additionally, the one patient of the Cinryze.RTM. cohort who
displayed CG had an adverse event of hemorrhagic shock after a
biopsy while receiving anti-coagulation medicine. FIGS. 9A and 9B
graphically correlate the baseline corrected C1-INH antigen levels
to CG in patients receiving placebo (FIG. 9A) and Cinryze.RTM.
(FIG. 9B). FIGS. 9C and 9D graphically correlate the baseline
corrected functional C1-INH levels to CG in patients receiving
placebo (FIG. 9C) and Cinryze.RTM. (FIG. 9D). FIGS. 9E and 9F
graphically correlate the unadjusted C1-INH antigen levels to CG in
patients receiving placebo (FIG. 9E) and Cinryze.RTM. (FIG. 9F).
FIGS. 9G and 9H graphically correlate the unadjusted functional
C1-INH levels to CG in patients receiving placebo (FIG. 9G) and
Cinryze.RTM. (FIG. 9H). The C1-INH antigen levels reported are
based on a measurement of protein weight concentration with
conversion to U/mL using the conversion factor of 0.067 U/ml=1 mg/1
dL.
[0022] FIGS. 10A and 10B graphically illustrate the effect of
plasmapheresis on serum C1-INH antigenic (FIG. 10A) and functional
(FIG. 10B) levels. As demonstrated in FIGS. 10A and 10B,
plasmapheresis depleted serum C1-INH antigenic and functional
levels.
DETAILED DESCRIPTION OF THE INVENTION
[0023] Antibody-mediated rejection (AMR) is implicated in foiling
the transplantation of, for example, heart, lung, liver, pancreas,
intestine and kidney allografts in patients. Because there are few
experimental and no approved therapies for antibody-mediated
rejection (AMR) and outcomes for transplants are strictly monitored
by the Centers for Medicare and Medicaid (CMS), patients awaiting
organ transplants with DSA are generally prohibited by most
transplant centers from receiving donor organs to which they are
sensitized. For example, every year several thousand end-stage
renal disease (ESRD) patients are prohibited from receiving a
potentially life-saving kidney transplant because of a pre-existing
antibody (DSA) directed against the donor's cell surface human
leukocyte antigens (HLA).
[0024] The presence of these circulating DSA, identified through
pre-transplant cross-match screening (complement-dependent
cytotoxicity assay or flow cytometry), is a contraindication to
transplantation. DSA can cause immediate, or "hyperacute,"
antibody-mediated rejection (AMR) resulting in complement-mediated
destruction and ultimately, loss of the transplanted organ.
[0025] Nearly one third of individuals on the kidney transplant
waiting list in the United States (US) have circulating antibodies
directed against .gtoreq.10% of the population HLA. These
sensitized patients spend a significantly longer time waiting for
an acceptable kidney to which they are not sensitized (i.e.,
"cross-match negative") for transplantation as compared to
non-sensitized patients. In the US, it is estimated that 6,000 ESRD
(wait list) patients and an additional 3,500 new wait list
registrants per year have a willing live donor but cannot be
transplanted due to sensitization or blood type incompatibility.
The inability to transplant sensitized patients with kidneys from
willing live donors further increases the demand for deceased donor
kidneys, and thus, increases wait times for all listed
patients.
[0026] Accreditation of kidney transplant programs by the US
Centers for Medicaid and Medicare Services (CMS) is based primarily
on a specific center's outcomes meeting or exceeding national
benchmarks for kidney transplantation (1-year graft survival rates
of .about.95%). When a program's death or graft failure rate
exceeds 150% of expected rates, the program is cited for
non-conformance and can lose CMS certification to perform kidney
transplants (see 42 CFR Part 482, .sctn. 482.80 and .sctn. 482.82
[2007]). Therefore, there is an unwillingness to perform kidney
transplants in highly sensitized or cross-match positive patients.
These patients, many of whom have a willing live donor, unduly
burden the deceased donor wait list and many will die waiting for a
transplant. However, an agent that is a useful therapy and/or
adjunct for desensitized patients in the prevention or treatment of
acute AMR may help change paradigms in transplantation, not only
permitting access to potentially life-saving transplants, but also
decreasing the wait list competition for those without a potential
living donor.
[0027] Decreasing DSA titers in cross-match positive or otherwise
sensitized patients through the use of intravenous immunoglobulin
(IVIg) or a combination of plasmapheresis and IVIg has allowed for
"desensitization" and conversion to negative cross-match for
successful kidney transplantation in some patients.
[0028] However, despite such protocols, more than 10% of patients
will lose their graft immediately or very early after
transplantation due to hyperacute rejection or aggressive acute
AMR. Moreover, 30%-50% of patients will still experience acute AMR,
most within the first 1 to 3 months post-transplantation. In fact,
1-year graft survival was 60%-70% in patients with DSA and AMR
compared to approximately 95% in patients with no DSA.
Nevertheless, for some patients, the morbidity and mortality rates
associated with dialysis warrant the risks of cross-match positive
kidney transplantation. There remains an unmet need to improve
overall outcomes for these high risk (cross-match positive)
transplant patients.
[0029] Acute AMR is routinely treated with additional IVIg and
plasmapheresis. However, approximately half of the patients
diagnosed with early acute AMR suffer irreversible damage to their
renal allograft as evidenced by transplant glomerulopathy (TG),
which is often associated with interstitial fibrosis,
glomerulosclerosis, and fibrointimal thickening. TG is a subset of
CG since TG refers to glomerulopathy occurring specifically in the
transplanted organ. Treatments such as IVIg and/or plasmapheresis
provided short-lived activity as opposed to long-lasting
therapeutic effect because such treatments eventually lose their
effectiveness. As used herein the term "short-lived activity"
refers to the activity of a treatment type against AMR that remains
effective only while receiving the interventional therapy. In
contrast, the term "long-lasting therapeutic effect" refers to the
activity of a treatment type against AMR that remains effective
from greater than about 3 to 6 months after cessation of
therapy.
[0030] Patients with the foregoing features of TG have greatly
impaired graft survival compared with patients who have no evidence
of TG on biopsy. Some patients with severe acute AMR may require
salvage therapy inclusive of rituximab (anti-CD20 antibody) and/or
bortezomib (proteasome inhibitor) with or without splenectomy as a
last treatment option. There remains an enormous unmet need for an
agent that effectively treats acute AMR (lessening the need for
drastic measures such as splenectomy) and improves overall graft
survival so that sensitized ESRD patients may be granted access to
transplantation after desensitization for a positive
cross-match.
[0031] Turning to the development of therapies that may overcome
the failings in the field, improvement of current AMR therapies
requires addressing the underlying host immune response that leads
to DSA-mediated TG and eventual loss of the allograft.
Plasmapheresis and IVIg can decrease DSA titers. However, their use
may not address the tissue destruction that occurs as a result of
complement activation. HLA-DSA complexes activate the classical
pathway of the complement cascade, ultimately resulting in the
formation of membrane attack complexes and continuous release of
inflammatory cytokines. As evidence of the role of complement in
graft destruction, accumulation of the 4th complement protein
degradation product (C4d) along peritubular capillaries (PTC) is
predictive of AMR and associated with poor allograft survival.
After adjusting for risk factors commonly associated with graft
failure, patients who require renal allograft biopsy for decreased
kidney function and had DSA in their serum with C4d staining on
biopsy have a risk of graft loss that is three times higher than
patients without DSA or C4d staining on biopsy. Therefore, a
complement inhibitor would prove a useful therapy and/or adjunct in
the treatment of AMR.
[0032] Transplantation of a vascularized allograft involves
exposure of the recipient to donor HLA. Processing and presentation
of donor HLA determine the recipient's immune response to the
transplanted allograft. If soluble donor antigen is presented and
recognized by a recipient's CD4 T-lymphocytes, cytokine release
(e.g., IL-2) will propagate a cytotoxic T-cell response resulting
in acute cellular rejection. B-lymphocyte recognition of donor HLA
results in propagation of a memory B-cell response and production
of DSA. HLA-DSA complexes stimulate the classical pathway of the
complement system resulting in antibody-mediated rejection (FIG.
1).
[0033] DSA can complex with the first component of the classical
complement pathway (C1) resulting in activated C1q/r/s and C4,
eventually resulting in the formation of membrane attack complexes
(C5b-9) and inflammatory cytokine release. These cytokines (e.g.,
IL-2, IL-6, and others) summon neutrophils and other mediators (for
example, platelet derived growth factor) to illicit a local
inflammatory response that can lead to fibrosis (irreversible
scarring) of tissues, endothelial response, and injury resulting in
coagulation and thrombosis of capillaries and larger vessels within
the graft. The extent and immediacy of the damage is dependent upon
whether (and to what extent) the DSA is pre-existing.
[0034] Donor HLA recognition by pre-existing DSA (with activation
of the classical complement pathway) results in immediate
(hyperacute) or early (within 1-3 months--accelerated) loss of the
transplanted allograft. Such pathology may be temporarily
alleviated by pre-transplant desensitization protocols (e.g.,
plasmapheresis and/or IVIg) directed at amelioration of DSA, but
providing only short-lived activity in approximately 50% of such
patients.
[0035] Additionally, clinical evidence indicates that patients who
require renal allograft biopsy for decreased kidney function and
have DSA in their serum with C4d staining (evidence of complement
activation) on renal allograft biopsy have a risk of graft loss
three times higher than patients without DSA or C4d staining on
biopsy. Data from animal models also support the role of complement
in allograft rejection. In a study of allotransplantation in
Cynomolgus monkeys, among animals with known DSA, 54% of monkeys
with C4d present on histopathology developed TG, compared with a TG
rate of only 4% in transplanted monkeys with no evidence of C4d on
biopsy.
[0036] Terminal complement (C5b-9) proteins (the product of
antibody mediated classical complement pathway activation) can
elicit production of fibroblast and platelet-derived growth factors
from endothelial cells, causing intimal fibrosis, a hallmark of
irreversible kidney transplant rejection. A preclinical mouse model
of sensitized kidney transplantation showed improved graft survival
in animals receiving a C5 inhibitor as adjunctive
immunosuppression. In a study of 16 sensitized human kidney
transplant recipients given the anti-05 monoclonal antibody
eculizumab after transplantation, only 1/16 (6%) developed acute
AMR within the first month after transplant compared with
.about.40% of historical controls. However, all had persistent C4d
staining and 4/16 (25%) had significant changes consistent with
TG/endothelial cell activation. Long term follow up revealed that
nearly 50% of these patients had TG after cessation of therapy, not
different than the historical control.
[0037] More proximal signalling components of the classical
complement cascade may have a greater role in alloimmunity. For
instance, mice deficient in complement protein C3 or C4 had
impaired T-cell and B-cell alloimmune responses to major
histocompatability complex disparate skin grafts, while
CS-deficient mice did not exhibit an impaired alloimmune response.
Accordingly, there is a greater theoretical efficacy of C1-INH over
a CS inhibiting agent for prevention or treatment of AMR. The
present invention provides such a therapy, utilizing a C1-INH
treatment that provides long-lasting therapeutic effect that meets
the needs in the field.
[0038] The present invention relates to methods for treating
antibody-mediated rejection (AMR) of an organ allograft in a
patient in need thereof, where the method includes administering a
therapeutically effective amount of a C1-esterase inhibitor
(C1-INH). The organ allografts that may be preserved from rejection
by the methods described herein include solid organs.
Representative examples of solid organs include heart, liver, lung,
pancreas, intestine, and kidney. In certain embodiments, the solid
organ may be kidney. In the method of the invention, the organ
transplantation includes allotransplantation. By way of
explanation, allotransplantation differs substantially from
xenotransplantation. Allotransplation involves transplantation of
organs that are from the same species (human-to-human transplant).
In contrast, xenotransplantation involves transplantation of organs
that are from differing species (e.g., pig-to-human organ
transplant). Those having ordinary skill in the relevant art would
recognize that cessation of C1-INH therapy would result in
immediate AMR in xenotransplantation. However, this is irrelevant
in human allotransplantation as there is no cross species
sensitization.
[0039] As used herein, the terms "treatment," "treating," and the
like refer to means for obtaining a desired pharmacologic or
physiologic effect, for example. The effect may be prophylactic in
terms of completely or partially preventing a condition,
appearance, disease, or symptom and/or may be therapeutic in terms
of a partial or complete cure for a condition and/or adverse effect
attributable to a condition or disease. Without being limited to
any one theory of operation, the methods of the invention are
believed prevent and/or treat AMR in organ transplants by
inhibiting components of the complement system.
[0040] Additionally, the term "short term duration" as used with
respect to treatment, refers to the duration of drug treatment
activities which may advantageously occur from about 1 to 30 days.
In certain aspects, the short term duration of treatment may be
about 10 to 20 days. In a preferred aspect, the short term duration
of treatment may be about 13 days.
[0041] The term "early" as used herein regarding treatment, refers
to the timing of treatment that may advantageously occur or be
initiated within 1 to 90 days of: (1) organ transplantation, (2)
treatment with the standard of care (plasmapheresis and/or IVIg),
and/or (3) diagnosis of AMR. In preferred aspects, the treatment
may occur or be initiated in less than about 5 to 10 days.
[0042] "Chronic glomerulopathy" or "CG" is a clinical marker of AMR
in an organ transplant patient and, as used herein, refers to
deleterious manifestations found in renal tissue including, for
example, glomerulsclerosis, glomerular basement membrane thickening
and lamination, and/or ongoing inflammation of the glomeruli.
Peritubular vasculitis may also be present.
[0043] The term "transplant glomerulopathy" or "TG" as used herein
refers to chronic glomerulopathy (CG) that occurs in the transplant
setting. TG and CG may used interchangeably to describe the
invention.
[0044] C1 esterase inhibitor (C1-INH) is an endogenous plasma
protein in the family of serine protease inhibitors (SERPINs) and
has broad inhibitor activity in the complement, contact, and
coagulation pathways. C1-INH inhibits the classical pathway of the
complement system by binding C1r and C1s and inhibits the
mannose-binding lectin-associated serine proteases in the lectin
pathway. The C1-INH of the present invention may be a plasma
derived C1-INH or may be recombinantly produced C1-INH. Preferably,
the C1-INH of the invention is a plasma derived C1-INH.
[0045] The term "Units" or "U" as used herein refers to the measure
of protein (C1 INH) material, that is normalized to physiologic
levels in human (i.e. 1 U/mL of serum is physiologic). In the
alternative, one (1) Unit denotes 240 .mu.g of protein material
unless otherwise indicated.
[0046] A nanofiltered plasma derived C1-INH (Cinryze.RTM.;
Viropharma) is FDA approved for routine prophylaxis against
angioedema attacks in adolescent and adult patients with hereditary
angioedema (HAE), a disease characterized by constitutional
deficiency or dysfunction of endogenous C1 esterase inhibitor.
[0047] Cinryze.RTM. is known to be well tolerated in humans via the
experience in patients with HAE studied in randomized trials as
well as in an extension trial. The most frequent adverse events
reported at the doses used for HAE were headaches and
nasopharyngitis. C1-INH is an ideal therapeutic, either alone or as
part of a combination therapy or composition, for diseases that
implicate, for example, the classical complement pathway (e.g.,
antibody-mediated diseases) and of the lectin pathway (e.g.,
ischemia reperfusion injury).
[0048] The term "effective amount," as used herein, refers to the
quantity of a compound or composition that achieves a beneficial
clinical outcome when the compound or composition is administered
to a patient. For example, when a composition of the invention is
administered to a patient with, for example, AMR, a "beneficial
clinical outcome" includes increased and/or sustained renal
function and/or an increase in the longevity of the patient's
allograft (e.g., transplanted kidney). As used herein, the term
"renal function" is defined with respect to the ability of a
patient's kidneys to clear creatinine from the body. Thus, for
example, a patient demonstrating increased renal function would
present with certain creatinine clearance ability (mL/min) (i.e.,
baseline) and such creatinine clearance ability or renal function
would increase in magnitude from the baseline during treatment and
after treatment.
[0049] The term "isolated," as used herein in describing a
material, for example, refers to material removed from its original
environment (e.g., the natural environment if it is naturally
occurring). For example, a naturally-occurring polypeptide (i.e.,
protein) present in a living animal is not isolated, but the same
polypeptide, separated from some or all of the coexisting materials
in the natural system, is isolated.
[0050] Moreover, the "polypeptides" or "proteins" used in
practicing the present invention may be natural proteins,
synthesized proteins, or may be preferably recombinant proteins.
Further, the proteins described herein can be naturally purified
products, or chemically synthesized products, or recombinant
products from prokaryotic or eukaryotic hosts (e.g., bacteria,
yeast, higher plant, insect, or mammalian cell). Such proteins can
be glycosylated or non-glycosylated according to the different
hosts used.
[0051] Turning to the recombinant proteins used in practicing the
invention, the recombinant C1-INH (rC1-INH) proteins can be
expressed or produced by conventional recombinant DNA technology,
using a polynucleotide sequence specific to C1-INH as known in the
art. Generally, such recombinant procedure comprises the following
steps:
[0052] (1) transfecting or transforming the appropriate host cells
with the polynucleotide or its variants encoding C1-INH protein of
the invention or the vector containing the polynucleotide;
[0053] (2) culturing the host cells in an appropriate medium;
and
[0054] (3) isolating or purifying the protein from the medium or
cells.
[0055] In practice, the agents of the invention may be administered
as separate dosage units or formulated for administration together,
according to procedures well known to those skilled in the art.
See, for example, Remington: The Science and Practice of Pharmacy,
20.sup.th ed., A. Genaro et al., Lippencot, Williams & Wilkins,
Baltimore, Md. (2000).
[0056] Suitable methods of introduction of compositions of the
invention to a patient include but are not limited to intradermal,
intramuscular, intraperitoneal, intravenous, subcutaneous,
intranasal, intraocular, epidural, and oral routes. Moreover,
compositions of the invention may be administered by infusion or
bolus injection, by absorption through epithelial or mucocutaneous
linings (e.g., oral mucosa, rectal, and intestinal mucosa, etc.).
Administration may further be systemic or local. And administration
can be acute or chronic (e.g., daily, weekly, monthly, etc.).
[0057] The orally administered dosage unit may be in the form of
tablets, caplets, dragees, pills, semisolids, soft or hard gelatin
capsules, aqueous or oily solutions, emulsions, suspensions or
syrups. Representative examples of dosage forms for parenteral
administration include injectable solutions or suspensions,
suppositories, powder formulations, such as microcrystals or
aerosol spray. The composition may also be incorporated into a
conventional transdermal delivery system.
[0058] In the methods disclosed herein, the compositions of the
invention may be administered at a dose in range from about 10
Units (U) of composition per kg body weight (U/kg) to about 250
U/kg. A dose of from about 25 to 150 U/kg, and preferably from
about 50 to 125 U/kg per day or, preferably, every other day of
treatment should be effective to produce the desired result. By way
of example, a suitable dose for IV administration would include an
initial intravenous infusion of about 100 U/kg on day 1, followed
by 50 U/kg on day 3. The compounds used in the method of the
invention may typically be administered from 1-4 times a day or
every other day, so as to deliver the above-mentioned dosage
regimen.
[0059] Additionally, dosage of the compositions of the invention
may be expressed as an amount of compound or composition divided
equally or unequally over a course of treatment. For example, a
course of treatment may last from about 1 to 30 days and about
1,000 to 25,000 units (U) of composition may be administered in
divided doses over that course of treatment. In certain aspects,
about 5,000 to 20,000 Units of composition may be administered by
IV in divided doses over 10 to 20 days or, preferably, 13 days.
However, the exact regimen for administration of the compounds
described herein will necessarily be dependent on the needs of the
individual subject being treated, the type of treatment
administered and the judgment of the attending medical specialist.
As used herein, the terms "subject" and "patient" includes both
humans and animals. As those skilled in the art will appreciate,
the dosage actually administered will depend upon the condition
being treated, the age, health and weight of the recipient, the
type of concurrent treatment, if any, and the frequency of
treatment. Moreover, the effective dosage amount may be determined
by one skilled in the art on the basis of routine empirical
activity testing to measure the bioactivity of the compound(s) in a
bioassay, and thus establish the appropriate dosage to be
administered.
[0060] Additionally, in the methods of the invention, compositions
may be administered as an adjunct to plasmapheresis therapy and/or
IVIg. For example, in an exemplary method of the invention a
composition including C1-INH (e.g., Cinryze.RTM.) may be
administered to a patient as 20,000 units provided in divided doses
(each dose not exceeding about 100 U/kg) over 10 to 20 days as an
adjunct to plasmapheresis and/or IVIg. Such treatment may reduce
the rate of chronic AMR at 3-6 months after cessation of
therapy.
[0061] In certain situations, compounds (e.g., C1-INH) used in
practicing the invention may be delivered as pharmaceutical
compositions that include a pharmaceutically acceptable carrier
medium. For example, the invention includes a pharmaceutical
composition for treating or delaying the progression of
antibody-mediated rejection (AMR) of an organ allograft in a
patient in need thereof, the composition including a C1-esterase
inhibitor (C1-INH); an additional biologically active agent, such
as an anti-lymphocyte preparation, rituximab, bortezomib,
eculizumab, immunoglobulin (Ig), or a combination thereof; and a
pharmaceutically acceptable carrier medium.
[0062] As used herein, the expression "pharmaceutically acceptable
carrier medium" includes any and all solvents, diluents, or other
liquid vehicle, dispersion or suspension aids, surface agent
agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants, fillers and the like as
suited for the particular dosage form desired. Remington: The
Science and Practice of Pharmacy, 20th edition, A. R. Genaro et
al., Part 5, Pharmaceutical Manufacturing, pp. 669-1015 (Lippincott
Williams & Wilkins, Baltimore, Md./Philadelphia, Pa.) (2000))
discloses various carriers used in formulating pharmaceutical
compositions and known techniques for the preparation thereof.
Except insofar as any conventional pharmaceutical carrier medium is
incompatible with the compositions described herein, such as by
producing an undesirable biological effect or otherwise interacting
in an deleterious manner with any other component(s) of a
formulation comprising the active agent(s), its use is contemplated
to be within the scope of this invention.
[0063] More specifically, in the production of solid dosage forms
the pharmaceutical composition may be mixed with pharmaceutically
inert, inorganic or organic excipients, such as lactose, sucrose,
glucose, gelatine, malt, silica gel, starch or derivatives thereof,
talc, stearic acid or its salts, dried skim milk, vegetable,
petroleum, animal or synthetic oils, wax, fat, polyols, and the
like. Liquid solutions, emulsions or suspensions or syrups one may
use excipients such as water, alcohols, aqueous saline, aqueous
dextrose, polyols, glycerine, lipids, phospholipids, cyclodextrins,
vegetable, petroleum, animal or synthetic oils. Suppositories may
include excipients, such as vegetable, petroleum, animal or
synthetic oils, wax, fat and polyols. Aerosol formulations may
include compressed gases suitable for this purpose, such as oxygen,
nitrogen and carbon dioxide. The pharmaceutical composition or
formulation may also contain one or more additives including,
without limitation, preservatives, stabilizers, e.g., UV
stabilizers, emulsifiers, sweeteners, salts to adjust the osmotic
pressure, buffers, coating materials and antioxidants.
[0064] The present invention further provides controlled-release,
sustained-release, or extended-release therapeutic dosage forms for
the pharmaceutical composition, in which the composition is
incorporated into a delivery system. This dosage form controls
release of the active agent(s) in such a manner that an effective
concentration of the active agent(s) in the bloodstream can be
maintained over an extended period of time, with the concentration
in the blood remaining relatively constant, to improve therapeutic
results and/or minimize side effects. Additionally, a
controlled-release system would provide minimum peak to trough
fluctuations in blood plasma levels of the active agent of the
invention.
[0065] Additionally, various delivery systems are known and can be
used to administer compositions that comprise C1-INH, or C1-INH in
combination with a biologically active agent, such as
immunoglobulin (Ig), rituximab, bortezomib and/or eculizumab, for
example. Additionally, such compositions may, for example, be
encapsulated in liposomes, microparticles, and microcapsules, for
example.
[0066] The methods of the present invention will normally include
medical follow-up to determine the therapeutic or prophylactic
effect brought about in the patient undergoing treatment with the
compound(s) and/or composition(s) described herein.
[0067] The results of the experiments described in the following
example demonstrate that commercially available plasma-derived
C1-INH can treat or prevent organ transplant rejection in patients
exhibiting AMR. This example is provided for illustrative purposes
only and is not intended to limit the invention in any way.
EXAMPLES
[0068] A randomized, double-blind, placebo-controlled pilot study
was used to evaluate the safety and effect of Cinryze.RTM. (C1
esterase inhibitor [human]) for the treatment of acute
antibody-mediated rejection in recipients of donor-sensitized
kidney transplants. The objectives of the study were: (a) to assess
the safety and tolerability of Cinryze.RTM. in kidney transplant
patients with acute antibody-mediated rejection (AMR); (b) to
assess the effect of Cinryze.RTM. for the treatment of acute AMR in
kidney transplant patients; and (c) to examine the pharmacokinetics
and pharmacodynamics of Cinryze.RTM. in kidney transplant patients
with acute AMR.
[0069] In the present study, there were no discontinuations of
treatment, no deaths, and no study drug related serious adverse
events.
[0070] Cinryze.RTM. was supplied as a lyophilized powder of 500 U
(C1-INH)/vial. Cinryze.RTM. product and sterile water for injection
approved for commercial distribution were utilized. Each vial of
Cinryze.RTM. was reconstituted with sterile water for injection(s).
Placebo consisted of 0.9% sodium chloride for infusion.
[0071] Dosing.
[0072] Subjects received a total of 7 doses of study drug
(Cinryze.RTM. or placebo) over a 2-week period (FIG. 2): an initial
intravenous (IV) infusion of 5000 U Cinryze.RTM. (not to exceed 100
U/kg) or placebo on Day 1, followed by 2500 U of Cinryze.RTM. (not
to exceed 50 U/kg) or placebo IV on Days 3, 5, 7, 9, 11, and 13. If
plasmapheresis therapy occurred on the same day as study drug
dosing, study drug was administered after completion of the
plasmapheresis session.
[0073] Study Design.
[0074] The study assessed the safety and effect of Cinryze.RTM. in
the treatment of acute AMR in HLA donor-sensitized kidney
transplant recipients (FIG. 2). To minimize variability, the study
was conducted only at institutions that use plasmapheresis and/or
intravenous immunoglobulin (IVIg), if necessary, for
desensitization of DSA positivity and treatment of acute AMR.
Subjects of the study had a kidney transplant that achieved
adequate post-transplant function and a first ("qualifying")
episode of biopsy-proven AMR with concurrent DSA identified prior
to or after the most current renal allograft.
[0075] As illustrated in FIG. 2, post-treatment evaluations were
performed on Day 20 and Day 90. The end of the study was defined as
the date that the last subject completed the Day 90 evaluation.
Complement and C1-INH levels were assessed at specified time points
up to Day 20 for PK/PD determinations. In addition, an optional
PK/PD sampling time point was included for Day 25. Additionally, at
6 months post-treatment an additional evaluation was provided from
14 equally randomized subjects (n=7 placebo; n=7 Cinryze) treated
similarly at a single transplant center to determine clinical
outcome.
[0076] Study Drug Administration.
[0077] Based on available preclinical and clinical data, the
physiologic levels of C1-INH sufficient for complement pathway
inhibition elicited by antigen-antibody complexes are at least 100%
above normal values. Following IV administration of 2000 U of
Cinryze.RTM. in healthy subjects, the mean change from baseline in
functional C1-INH activity was approximately 50-60%. Given that 1 U
of C1-INH activity is found in 1 mL of plasma, to increase the
functional activity of C1-INH by at least 100% in patients with
acute AMR, a dose of about 5000 U may be required in an average
adult. Given that Cinryze.RTM. has a half-life of about 60 hours in
HAE patients, subsequent doses of 2500 U given every other day may
maintain adequate functional C1-INH levels throughout the dosing
period. Therefore, subjects randomized to the Cinryze.RTM. group in
this study will receive a loading dose of 5000 U (not to exceed 100
U/kg) followed by 2500 U (not to exceed 50 U/kg) every other day
for a total of 7 doses. This regimen balances the apparent
dose-dependent nature of inhibiting complement activation elicited
by antigen-antibody complexes, while minimizing the potential risk
of coagulation observed in preclinical and clinical studies with
other C1-INH compounds at doses .gtoreq.200 U/kg.
[0078] As set forth above, a total of 7 doses of Cinryze.RTM. or
placebo (0.9% sodium chloride solution for infusion) were
administered as follows: (a) an initial dose of 5000 U of
Cinryze.RTM. (not to exceed 100 U/kg) or placebo as a single IV
infusion on Day 1; and then (b) 2500 U of Cinryze.RTM. (not to
exceed 50 U/kg) or placebo IV every other day for 2 weeks (Days 3,
5, 7, 9, 11, and 13). Each dose of study drug was to be
administered IV at a rate of approximately 1 mL (corresponding to
100 U of Cinryze.RTM.) per minute as tolerated. Therefore, the
duration of the 5000 U (50 mL) infusion on Day 1 was to be
approximately 50 minutes and the duration of the 2500 U (25 mL)
infusions on Days 3, 5, 7, 9, 11, and 13 was to be approximately 25
minutes. The `start` and `stop` times and dates of each study drug
infusion was to be recorded.
[0079] Plasmapheresis, Fresh Frozen Plasma, and IVIg.
[0080] Plasmapheresis therapy was to be performed for the
qualifying episode of AMR. Regardless of plasmapheresis schedule,
study drug was to be administered on Days 1, 3, 5, 7, 9, 11, and
13. Moreover, as demonstrated in FIG. 3, certain patients were
provided with, as necessary, the standard of care that included
plasmapheresis, plasma replacement in the form of fresh frozen
plasma (FFP), blood, and/or IVIg (e.g., cytogam, gamunex,
etc.).
[0081] Pharmacokinetics/Pharmacodynamics.
[0082] In the present study, an analysis of the pharmacokinetics
and pharmacodynamics of Cinryze.RTM. were undertaken with respect
to placebo. With respect to pharmacokinetic analyses, C1-INH
antigen and functional levels for individual subjects were
determined. Primary PK parameters were calculated using
baseline-corrected concentration-versus-time data following the
last dose (Day 13) and noncompartmental techniques, as appropriate.
Levels of C1-INH functional were analyzed in patients receiving
C1-INH or placebo over the entire treatment time course (FIG. 4A).
As expected, the cohort mean amount of C1-INH functional corrected
for baseline levels was greater in patients receiving C1-INH
(Cinryze.RTM.) on days 3, 5, 7, 9, 11, and 13. Additionally, the
difference in mean baseline corrected plasma concentration of
C1-INH functional is apparent at day 13 when the concentration was
measured over a shorter time course (FIG. 4B). Thus, in patients
treated with Cinryze.RTM. and plasmapheresis (and/or IVIg), there
was a greater concentration of C1-INH functional (i.e., active
classical complement pathway inhibitor protease) when compared to
placebo (i.e., plasmapheresis (and/or IVIg) alone).
[0083] With respect to pharmacodynamic analyses, complement C1 q,
C4, and C4a levels for individual subjects were evaluated. Blood
samples for the determination of plasma concentrations of C1-INH
functional and antigenic and complement components C1q, C4, and C4a
were collected (Table 1). If plasmapheresis was to be performed on
a dosing day, blood samples for PK/PD testing was to be obtained
before plasmapheresis, as well as prior to study drug
administration (i.e., post-plasmapheresis), and at time points
relative to the start of the study drug infusion.
TABLE-US-00001 TABLE 1 Study of the Pharmacokinetic and
Pharmacodynamic effects of Cinryze .RTM. with respect to Placebo
Cinryze .RTM. Placebo Antigen (U/mL) 0.477 0.118 Function (U/mL)
0.994 0.309 C1q (.mu.g/mL) 37.9 17.2 C4 (ng/mL) 113 70 C4a (ng/mL)
55 400
[0084] With respect to Table 1, Cinryze.RTM. patients exhibited
increased C1-INH functional and classical complement system
inhibition where baseline levels were subtracted for calculation of
the mean to demonstrate the overall effect of study drug therapy in
each cohort. Compared to placebo, Cinryze.RTM. patients
demonstrated increased levels (above baseline entry levels) of both
C1-INH antigenic and functional in plasma, indicating a greater
concentration of active and total C1-INH beyond the levels which
patients began their study dosing. The C1-INH antigen levels
reported are based on a measurement of protein weight concentration
with conversion to U/mL using the conversion factor of 0.067 U/ml=1
mg/1 dL (unless otherwise indicated). In fact the unadjusted range
(where baseline levels were not subtracted) for C1-INH functional
was 1.59-2.02 U/mL at the end of Cinryze.RTM. therapy. However,
this was not statistically different than the unadjusted range for
placebo treated patients. Nevertheless, there was a noticeable
cohort difference when examined for C1-INH above their entry
level.
[0085] Cinryze.RTM. patients exhibited evidence of systemic
inhibition of the complement system in the fluid phase. Patients
treated with Cinryze.RTM. exhibited an increased plasma
concentration (corrected for baseline entry levels) of C1q and C4,
which are classical complement pathway proteins that would show a
decreased concentration in plasma if the classical complement
pathway were uninhibited. However, since the concentration of C1q
and C4 is increased, this indicates some level of systemic
inhibition.
[0086] Finally, classical complement pathway inhibition is
confirmed by the decreased plasma concentration of C4a as compared
to placebo. Ordinarily, upon complement system activation C4 is
converted to C4a, thereby reducing the plasma concentration of C4.
The present analysis indicates that in patients treated with
additional exogenous C1-INH (Cinryze.RTM.) exhibited an increase in
C1-INH functional protein that apparently led to systemic
complement system inhibition.
[0087] In examining the physiological effects of C1-INH treatment,
FIG. 5 discloses differences in mean renal function (i.e.,
creatinine clearance) between the cohort of patients treated with
Cinryze.RTM. or placebo in combination with plasmapheresis (and/or
IVIg) over the 13 day time course.
[0088] Chronic glomerulopathy (CG) is a clinical marker of AMR in a
transplant patient. FIG. 6A represents normal renal tissue at six
months. FIG. 6B demonstrates CG as a result of ongoing AMR. In
those patients treated with placebo, 3 of 7 displayed CG, whereas,
in those patients treated with Cinryze.RTM., only 1 of 7 displayed
CG. These tissue studies were confirmed by electron microscopy (EM)
of obtained renal tissue (FIG. 7). FIG. 7A represents a normal EM
image of renal tissue whereas FIG. 7B represents an electron
micrograph of renal tissue having CG. Examining such electron
micrographs, it was determined that in those patients treated with
placebo as an adjunct to standard of care (plasmapheresis and/or
IVIg), 3 of 7 displayed pathology consistent with CG, whereas, in
those patients treated with Cinryze.RTM. as an adjunct to standard
therapy, 1 of 7 displayed pathology consistent with CG.
[0089] Additionally, the day 13 C1-INH antigen levels and
functional C1-INH levels in patients treated with placebo or
Cinryze.RTM. were correlated to the 6 month clinical outcomes of
the patients. The day 13 baseline adjusted (i.e., corrected), and
unadjusted, C1-INH antigen and functional levels were first
measured (FIG. 8). The data from these measurements were then
graphically correlated to the 6 month clinical outcomes of the same
patients (FIGS. 9A to 9H). As demonstrated in FIGS. 9A and 9B,
there was a lesser incidence of CG in those patients treated with
Cinryze.RTM. (FIG. 9B) as compared to those treated with placebo
(FIG. 9A) where the Cinryze.RTM. patients exhibited 14% CG and the
patients receiving placebo exhibited 43% CG.
[0090] At 6 months post-treatment it was also determined that those
patients demonstrating low C1-INH antigenic levels at day 13 above
their baseline entry levels also exhibit the presence of CG. Thus,
there was an observed correlation between baseline corrected C1-INH
antigen and the presence of CG in renal tissue.
[0091] Furthermore, serum C1-INH antigenic and functional levels
were depleted by plasmapheresis as demonstrated in FIGS. 10A and
10B. For instance, as shown in FIG. 10, plasmapheresis decreased
both the mean C1-INH angtigenic and functional levels by 17.6%
(FIG. 10A) and 43.3. % (FIG. 10B), respectively.
[0092] The present invention encompasses methods of using C1-INH
(e.g., Cinryze.RTM.) as a therapy and/or add-on therapy to standard
care (i.e., plasmapheresis and IVIg: both of which address donor
specific antibodies) for treating and/or preventing AMR in
transplant patients. An unexpected aspect of the instant invention
is that early and/or short-term duration treatment with C1-INH in
transplant patients results in longer term benefit after the C1-INH
treatment dosing has been discontinued.
[0093] Moreover, the dosing regimen provided unexpected benefits.
It is currently unknown if kidney transplant patients could ever
achieve a level of C1-INH functional protein sufficient enough to
effectively reduce complement activation systemically or within the
transplant allograft. Indeed, the dosage of 20,000 units given in
divided doses over 13 days was selected. This dose was
satisfactory, not only clinically, but also in the increase of
serum C1-INH functional levels above baseline.
[0094] Accordingly, the present study demonstrated that where
kidney transplant patients are treated with 20,000 Units of
Cinryze.RTM. over 13 days: (a) the dosage regimen was well
tolerated by the kidney transplant patients; (b) such patients
maintained supraphysiologic levels of C1-INH as a result of
Cinryze.RTM. treatment; (c) such patients demonstrated early
improvement in renal function; and (d) such patients demonstrated
less glumerulopathy at 6 months with respect to placebo. Therefore,
the treatment methodology tested provided long-lasting therapeutic
effect against AMR as compared to the treatments currently in the
field.
[0095] There are publications cited herein in order to describe the
state of the art to which this invention pertains. The entire
disclosure of each of these publications is incorporated by
reference herein.
[0096] While certain embodiments of the present invention have been
described and/or exemplified above, various other embodiments will
be apparent to those skilled in the art from the foregoing
disclosure. The present invention is, therefore, not limited to the
particular embodiments described and/or exemplified, but is capable
of considerable variation and modification without departure from
the scope and spirit of the appended claims.
[0097] Furthermore, the transitional terms "comprising",
"consisting essentially of" and "consisting of", when used in the
appended claims, in original and amended form, define the claim
scope with respect to what unrecited additional claim elements or
steps, if any, are excluded from the scope of the claim(s). The
term "comprising" is intended to be inclusive or open-ended and
does not exclude any additional, unrecited element, method, step or
material. The term "consisting of" excludes any element, step or
material other than those specified in the claim and, in the latter
instance, impurities ordinary associated with the specified
material(s). The term "consisting essentially of" limits the scope
of a claim to the specified elements, steps or material(s) and
those that do not materially affect the basic and novel
characteristic(s) of the claimed invention. All compositions and
methods described herein that embody the present invention can, in
alternate embodiments, be more specifically defined by any of the
transitional terms "comprising," "consisting essentially of," and
"consisting of."
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