U.S. patent application number 09/918343 was filed with the patent office on 2002-06-27 for methods for alleviating symptoms associated with diabetes and diabetic neuropathy comprising administration of low levels of antibodies.
Invention is credited to McMichael, John.
Application Number | 20020081300 09/918343 |
Document ID | / |
Family ID | 27118955 |
Filed Date | 2002-06-27 |
United States Patent
Application |
20020081300 |
Kind Code |
A1 |
McMichael, John |
June 27, 2002 |
METHODS FOR ALLEVIATING SYMPTOMS ASSOCIATED WITH DIABETES AND
DIABETIC NEUROPATHY COMPRISING ADMINISTRATION OF LOW LEVELS OF
ANTIBODIES
Abstract
The invention provides methods and compositions for alleviating
the symptoms of diabetes with a pharmaceutical composition
including a combination of anti-glutamic acid decarboxylase
(anti-GAD) and anti-insulin antibodies.
Inventors: |
McMichael, John; (Delanson,
NY) |
Correspondence
Address: |
MARSHALL, GERSTEIN & BORUN
6300 SEARS TOWER
233 SOUTH WACKER
CHICAGO
IL
60606-6357
US
|
Family ID: |
27118955 |
Appl. No.: |
09/918343 |
Filed: |
July 30, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09918343 |
Jul 30, 2001 |
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09774770 |
Jan 31, 2001 |
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6294171 |
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09774770 |
Jan 31, 2001 |
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09514993 |
Feb 29, 2000 |
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6187309 |
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60153838 |
Sep 14, 1999 |
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Current U.S.
Class: |
424/150.1 ;
424/145.1 |
Current CPC
Class: |
A61P 3/10 20180101; C07K
16/40 20130101; A61K 2039/505 20130101; A61P 25/14 20180101; C07K
16/26 20130101; A61P 25/00 20180101; A61P 25/28 20180101; C07K
16/1027 20130101 |
Class at
Publication: |
424/150.1 ;
424/145.1 |
International
Class: |
A61K 039/395 |
Claims
What is claimed is:
1. A method of alleviating symptoms of diabetes, comprising the
step of administering the combination of anti-glutamic acid
decarboxylase (anti-GAD) antibody and anti-insulin antibody in
amounts effective to alleviate symptoms of diabetes.
2. The method of claim 1, wherein the symptoms are selected from
the group consisting of elevated blood sugar level, elevated
hemoglobin A1c level, neuropathy, retinopathy, ketoacidosis, and
glycosuria.
3. The method of claim 1 wherein both anti-GAD and anti-insulin
antibodies are monoclonal antibodies.
4. The method of claim 1 wherein the administration step is
oral.
5. The method of claim 4 wherein the administration step is
sublingual.
6. The method of claim 4 wherein both anti-GAD and anti-insulin
antibodies are administered in an enterically protected form.
7. The method of claim 1 wherein the administration step is by
injection.
8. The method of claim 7 wherein the administration step is by
subcutaneous injection.
9. The method of claim 1 comprising less than 1.0 mg of anti-GAD
antibodies and less than 1.0 mg of anti-insulin antibodies.
10. The method of claim 9 comprising less than 0.1 mg of anti-GAD
antibodies and less than 0.1 mg of anti-insulin antibodies.
11. The method of claim 9 comprising from 1.times.10.sup.-6 to
1.times.10.sup.-2 mg of anti-GAD antibodies and 1.times.10.sup.-6
to 1.times.10.sup.-2 mg of anti-insulin antibodies.
12. The method of claim 9 comprising from 1.times.10.sup.-5 to
1.times.10.sup.-3 mg of anti-GAD antibodies and 1.times.10.sup.-5
to 1.times.10.sup.-3 mg of anti-insulin antibodies.
13. A pharmaceutical composition for administration to a subject
for alleviating symptoms of diabetes comprising less than 1.0 mg of
anti-GAD antibodies and less than 1.0 mg of anti-insulin
antibodies.
14. A pharmaceutical composition of claim 13 comprising less than
0.1 mg of anti-GAD antibodies and less than 0.1 mg of anti-insulin
antibodies.
15. A pharmaceutical composition of claim 13 comprising from
1.times.10.sup.-6 to 1.times.10.sup.-2 mg of anti-GAD antibodies
and 1.times.10.sup.-6 to 1.times.10.sup.-2 mg of anti-insulin
antibodies.
16. A pharmaceutical composition of claim 13 comprising from
1.times.10.sup.-5 to 1.times.10.sup.-3 mg of anti-GAD antibodies
and 1.times.10.sup.-5 to 1.times.10.sup.-3 mg of anti-insulin
antibodies.
Description
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 09/774,770 filed on Jan. 31, 2001 and issued
______ as U.S. Pat. No. ______, which is a continuation-in-part of
U.S. application Ser. No. 09/514,993 filed on Feb. 29, 2000 and
issued Feb. 13, 2001 as U.S. Pat. No. 6,187,309, which claims
benefit of U.S. Provisional Application Serial No. 60/153,838 filed
on Sep. 14, 1999; the disclosures of which are hereby incorporated
by reference.
BACKGROUND OF THE INVENTION
[0002] The therapeutic use of antibodies is generally limited to:
(a) immunotherapy, where a specific antibody directed against a
discreet antigen is used to counter the effect of that antigen,
e.g., using an antitoxin administered to neutralize a toxin, or
antibody against an infectious agent to interrupt the
pathophysiological process induced by that target organism; (b) the
administration, often i.v., of high levels of antibody (gamma
globulin therapy) to compensate for transient or permanent immune
deficiency; and (c) monoclonal antibody therapy to combat cancer,
certain autoimmune disorders and metabolic diseases. In all these
cases, antibody is provided in relatively high concentrations for
the purpose of having that antibody combine directly with its
target antigen to render that antigen inoperable, non-infectious or
neutralized. For example, Gamimune.TM. (Bayer Biological) contains
50 mg protein (immunoglobin) per mL and normal dosing can be up to
1000 mg/kg body weight. Gammar-P.TM. I.V. (Aventis Behring) is
administered at dosages up to 400 mg/kg body weight. Bayhep B.TM.
(Hepatitis B Immunoglobulin) (Bayer Biological) is 15-18% protein
[immunoglobulin] is administered at dosages of up to 0.6 ml/kg body
weight=0.01 g/kg=100 mg/kg. Further, Imogam Rabies-IIT.TM. (Aventis
Pasteur) is 10-18% protein and is administered at a dosage of 0.133
ml/kg (240 mg/kg) body weight.
[0003] Diabetes mellitus is a metabolic disease state that is
caused by a deficiency of insulin (Type I diabetes) or by the
body's resistance to diabetes (Type II diabetes). The disease is
characterized by chronic hyperglycemia, glycosuria, water and
electrolyte loss, ketoacidosis, neuropathy, retinopathy,
nephropathy, increased susceptibility to infection, and coma. Type
I diabetes results from the autoimmune destruction of beta cells of
the pancreas. Thus, proteins produced by beta cells have been a
prime target in the study of diabetes as potential autoantigens
that serve as the target for the immune response against the beta
cells. One autoantigen found to correspond to the onset of Type I
diabetes is glutamic acid decarboxylase (GAD) [Tisch, Roland, et
al., Nature, 366:72-75 (1993)]. Another example of a beta cell
autoantigen is insulin.
[0004] Much of the research involving the autoimmune response
against beta cells or the autoantigens thought to be involved in
the autoimmune response has included the administration of
autoantigens, immunogenic portions of autoantigens, or molecules
that mimic the autoantigens. Tian, Jide, et al.,Nat Med, 2(12):
1348-53 (1996) discusses administration of GAD to alter the diverse
immune response that can lead to diabetes. Ramiya, Vijayakumar K.,
et al., Autoimmunity, 26:139-151 (1997) discussed administration of
insulin and GAD in nonobese diabetic mouse to achieve anti-diabetic
affects.
[0005] Of interest to the present application is the disclosure of
co-owned U.S. Pat. No. 6,187,309, which is directed to the
administration of anti-rubeola antibodies for the treatment of
symptoms of various central nervous system diseases including
autism, multiple sclerosis, attention deficit disorder (ADD) and
attention deficit hyperactivity disorder (ADHD). Examples therein
demonstrated the efficacy of treating the symptoms of those disease
states with dosages of from 0.1 mg to 1 mg of anti-rubeola antibody
per dose.
[0006] While the administration of larger quantities of
immunoglobulins is effective in the treatment of many disease
states, there remains a desire in the art for methods for the
treatment and prevention of diabetes.
SUMMARY OF THE INVENTION
[0007] The present invention is directed to the discovery that the
symptoms of diabetes may be effectively treated by administration
of very low levels of a combination of anti-glutamic acid
decarboxylase (anti-GAD) antibodies and anti-insulin antibodies.
Specifically, the antibodies may be administered in one or in
multiple dosages but the sum of antibodies administered in any 24
hour period (or daily period) is less than 10 mg each of anti-GAD
and anti-insulin antibodies, with preferred daily dosages being
less than 1.0 mg and more preferably less than 0.1 mg.
[0008] While the antibody may be monoclonal or polyclonal, it is
preferably monoclonal according to one aspect of the invention. The
antibody maybe administered by a variety of manners but is
preferably administered subcutaneously and orally. Suitable methods
of oral administration include oral drench and sublingual
administration. According to another aspect of the invention the
antibody is administered in an enterically protected form.
[0009] The invention provides methods for treating the symptoms of
diabetes comprising the method of administering an effective amount
of a combination of an antibody directed against GAD and antibody
directed against insulin. The term "effective amounts of an
antibody" is used herein to describe the amount of antibody
administered to a subject to result in the reduction or elimination
of the pathogenic autoimmune response associated with the onset of
diabetes, thereby alleviating symptoms of diabetes. Preferred
amounts of anti-GAD and anti-insulin antibodies for use according
to the disclosed method are less than 1.0 mg of anti-GAD antibodies
and less than 1.0 mg of anti-insulin antibodies, and more
preferably less than 0.1 mg of anti-GAD antibodies and less than
0.1 mg of anti-insulin antibodies. A still more preferred daily
dosage ranges from 1.times.10.sup.-6 to 1.times.10.sup.-2 mg of
anti-GAD antibodies and 1.times.10.sup.-6 to 1.times.10.sup.-2 mg
of anti-insulin antibodies. An even more preferred daily dosage
ranges from 1.times.10.sup.-5 to 1.times.10.sup.-3 mg of anti-GAD
antibodies and 1.times.10.sup.-5 to 1.times.10.sup.-'mg of
anti-insulin antibodies.
[0010] The invention also provides pharmaceutical compositions for
administration to subjects for treatment of the symptoms of
diabetes comprising a dosage unit of less than 10 mg of anti-GAD
antibodies and less than 10 mg of anti-insulin antibodies. A
preferred dosage unit is less than 1.0 mg of anti-GAD antibodies
and less than 1.0 mg of anti-insulin antibodies, and more
preferably less than 0.1 mg of anti-GAD antibodies and less than
0.1 mg of anti-insulin antibodies. A still more preferred dosage
unit ranges from 1.times.10.sup.-6 to 1.times.10.sup.-2 mg of
anti-GAD antibodies and 1.times.10.sup.-6 to 1.times.10.sup.-2 mg
of anti-insulin antibodies. An even more preferred dosage unit
ranges from 1.times.10.sup.-5 to 1.times.10.sup.-3 mg of anti-GAD
antibodies and 1.times.10.sup.-5 to 1.times.10.sup.-3 mg of
anti-insulin antibodies.
DETAILED DESCRIPTION
[0011] The methods and compositions described herein relate to low
levels of antibodies specific for the autoantigens of pancreatic
beta cells that can reduce or eliminate the pathological
consequences caused by the autoimmune response against the
pancreatic beta cells. The mechanism by which this is accomplished
is not completely understood and is the focus of ongoing research.
Without intending to be bound by any particular theory of the
invention, it is thought that the low levels of the antibodies
specific for the autoantigens are able to prevent the pathogenic
cascade that results from the destruction of the autoantigens by
the immune system, possibly by redirecting the host immune system
or by providing a negative feedback to prevent further autoimmune
response. Particularly, the use of antibodies against GAD and
insulin can be used as a systemic signal to specifically inhibit
the body's aberrant, pathogenic response to the autoimmune response
against GAD and insulin. In addition to the use of the disclosed
method to alleviate symptoms of diabetes, it is further
contemplated that practice of the methods disclosed herein will
prove useful in the prevention of diabetes.
[0012] Antibodies of the invention can be produced using any method
well known and routinely practiced in the art. Such antibodies
include monoclonal and polyclonal antibodies, single chain
antibodies, chimeric antibodies, bifunctional/bispecific
antibodies, humanized antibodies, human antibodies, and
complementary determining region (CDR)-grafted antibodies,
including compounds which include CDR and/or antigen-binding
sequences, which specifically recognize a polypeptide of the
invention. A preferred anti-GAD antibody and anti-insulin antibody
is available from Chemicon International Inc., Temecula, Calif.
[0013] Symptoms of diabetes which can be treated according to the
methods of the invention include elevated blood sugar level,
elevated hemoglobin A1c level, neuropathy, retinopathy,
ketoacidosis, and glycosuria. With respect to blood sugar levels,
normal levels are <140 mg/dl, and diabetic levels are considered
to be levels >140 mg/dl.
[0014] The following examples are illustrative and are not intended
to limit either the scope or spirit of the invention.
EXAMPLES
EXAMPLE I
[0015] According to this example, low dosages of a combination of
anti-GAD and anti-insulin antibodies were administered to a 3-4
year old female cat with a blood glucose level of 352 mg/dl. The
cat experienced the traditional symptoms of diabetes, which
included weight loss and dehydration among others. Specifically,
the subject was treated by subcutaneous injection twice daily of
one dose of anti-GAD (8.times.10.sup.-4 mg) and anti-insulin
antibodies (4.times.10.sup.-4 mg). Antibodies used were sheep
polyclonal antibodies and both the anti-GAD and anti-insulin
antibodies were obtained from Chemicon International Inc.,
Temecula, Calif. In about 5 days the subject had a reduced blood
glucose level of 110 mg/dl. This treatment was stopped at day 10
with the subject having a blood glucose level of 82 mg/dl.
Subsequent testing of the subject showed that after about 3 weeks
after treatment was stopped, the subject was alleviated of diabetic
symptoms without subjection to additional therapy.
EXAMPLE II
[0016] According to this example, a spayed 10 year old Rottweiler
with insulin-dependent diabetes had required 42 units of insulin
twice daily. The subject had a blood glucose level of 371 mg/dl
even with the administration of insulin on day 1 of therapy with
anti-GAD and anti-insulin antibodies. The subject was treated by
subcutaneous injection twice daily of one dose of anti-GAD
(8.times.10.sup.-4 mg) and anti-insulin antibodies
(4.times.10.sup.-4 mg). The antibodies used in this example are the
same as that used above in Example I. After about 5 weeks of
treatment with decreasing insulin dosage, the subject had a reduced
blood glucose level of 165 mg/dl.
EXAMPLE III
[0017] According to this example, a 13 year old neutered male
domestic long hair cat experiencing anorexia, depression and having
collapsed was subjected to antibody therapy. The subject had a
blood glucose level of 473 mg/dl initially. The subject was treated
by subcutaneous injection twice daily of one dose of anti-GAD
(4.times.10.sup.-4 mg) and anti-insulin antibodies
(2.times.10.sup.-4 mg) in addition to insulin dosage of 1.3 units
twice daily. The antibodies used in this example are the same as
that used above in Example I. On day 13 the subject had a reduced
blood glucose level of 41 mg/dl in the morning and 44 mg/dl in the
afternoon, and the insulin dosage was reduced to 0.8 units twice
daily. On day 18 the subject had a blood glucose level of 81 mg/dl
and the insulin dosage was eliminated. After approximately 3 months
of antibody treatment and no insulin for about 1 month, the subject
had a blood glucose level of 99 mg/dl.
EXAMPLE IV
[0018] According to this example, a 8 year old neutered female
domestic shorthair cat had a blood glucose level of 369 mg/dl and
had undergone treatment with insulin, 3.0 units bid. With a blood
glucose level of 439 mg/dl, the subject underwent antibody therapy
comprising subcutaneous injection twice daily of one dose of
anti-GAD (8.times.10.sup.-4 mg) and anti-insulin antibodies
(4.times.10.sup.-4 mg). The antibodies used in this example are the
same as that used above in Example I. After about 3.5 weeks of
therapy, insulin treatment was reduced to 2.5 units bid. After 5
weeks the blood glucose level was reduced to 125 mg/dl. After about
4 months, the subject had a blood glucose level of 105 mg/dl. The
subject eventually was removed from insulin therapy and kept on low
level antibody therapy.
EXAMPLE V
[0019] According to this example, a 45 year old female diagnosed
with insulin-dependent diabetes was treated with low level
antibodies. The subject was determined to have a hemoglobin A1C
level of 11%, which is typically at a level of 4-6% in non-diabetic
individuals. The subject experienced neuropathy characterized by
numbness and poor circulation as determined by the subject in
response to a tuning fork test. The subject underwent antibody
therapy by sublingual administration, via drops, twice daily of one
dose of anti-GAD (8.times.10.sup.-4 mg) and anti-insulin antibodies
(4.times.10.sup.-4 mg). The antibodies used in this example are the
same as that used above in Example I. The subject was tested for
hemoglobin A1C levels after 2 weeks of therapy and the levels were
reduced to 7%. The subject was free from any other therapies during
the low level antibody therapy. After one week the subject
experienced a disappearance of neuropathy in the subject's lower
extremities. The low level antibody treatment was stopped and the
subject's previously experienced neuropathy returned after
approximately one week.
EXAMPLE VI
[0020] According to this example, a 42 year old female with a 20
year history of diabetes mellitus was treated with low level
antibodies. The subject was treated with antibody therapy by
sublingual administration in the form of 1 drop (or dose),
4.times.per day. Each dose contained 8.times.10.sup.-4 mg of
anti-GAD and 4.times.10.sup.-4 mg of anti-insulin antibodies. The
antibodies used in this example are the same as that used above in
Example I. After approximately one week, the subject experienced an
abatement of pain from diabetic neuropathy and a reduction in blood
sugar levels. Following a one week period in which the subject
experience no pain, the subject was discontinued from low level
antibody treatment. The discontinuation resulted in reoccurrence of
diabetic neuropathy and elevated blood sugar levels, which were the
symptoms experience by the subject prior to low level antibody
treatment. Subsequently, the subject was, again, treated with low
level antibody therapy, which resulted in abatement of pain from
diabetic neuropathy and a reduction in blood sugar levels similar
to the result from the initial therapy with low level
antibodies.
EXAMPLE VII
[0021] According to this example, a white male diagnosed with
diabetes was treated with low level antibodies. The subject was
treated with antibody therapy by sublingual administration in the
form of 1 drop (or dose), 2.times.per day. Each dose contained
8.times.10.sup.-4 mg of anti-GAD and 4.times.10.sup.-4 mg of
anti-insulin antibodies. The antibodies used in this example are
the same as that used above in Example I. After approximately eight
weeks the subject experienced a reduction in diabetic neuropathy of
approximately 60%. This reduction in diabetic neuropathy was
determined by having the patient assess the sensations resulting
from a tuning fork on the subject's lower extremities just prior to
treatment and after the eight weeks of treatment. Additionally, the
subject experienced a loss in weight (approximately 12 lbs),
increased energy and a reduction in levels of blood sugar of about
40 mg/dl.
[0022] Numerous modifications and variations in the practice of the
invention are expected to occur to those skilled in the art upon
consideration of the presently preferred embodiments thereof,
consequently, the only limitations which should be placed upon the
scope of the invention are those which appear in the appended
claims.
* * * * *