U.S. patent application number 13/556151 was filed with the patent office on 2013-01-24 for methods to facilitate transmission of large molecules across the blood-brain, blood-eye, and blood-nerve barriers.
This patent application is currently assigned to TACT IP LLC. The applicant listed for this patent is Edward Lewis Tobinick. Invention is credited to Edward Lewis Tobinick.
Application Number | 20130022540 13/556151 |
Document ID | / |
Family ID | 42196492 |
Filed Date | 2013-01-24 |
United States Patent
Application |
20130022540 |
Kind Code |
A1 |
Tobinick; Edward Lewis |
January 24, 2013 |
METHODS TO FACILITATE TRANSMISSION OF LARGE MOLECULES ACROSS THE
BLOOD-BRAIN, BLOOD-EYE, AND BLOOD-NERVE BARRIERS
Abstract
A method for delivering a biologic to a human, comprising
administering said biologic parenterally into the perispina! space
of said human without direct intrathecal injection and positioning
said human in a Trendelenburg position.
Inventors: |
Tobinick; Edward Lewis; (Los
Angeles, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Tobinick; Edward Lewis |
Los Angeles |
CA |
US |
|
|
Assignee: |
TACT IP LLC
Highland Beach
FL
|
Family ID: |
42196492 |
Appl. No.: |
13/556151 |
Filed: |
July 23, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12568661 |
Oct 19, 2009 |
8236306 |
|
|
13556151 |
|
|
|
|
11601799 |
Nov 17, 2006 |
7629311 |
|
|
12568661 |
|
|
|
|
11016047 |
Dec 18, 2004 |
7214658 |
|
|
11601799 |
|
|
|
|
Current U.S.
Class: |
424/1.49 ;
424/130.1; 424/133.1; 424/134.1; 424/142.1; 424/153.1; 424/94.64;
514/1.1; 514/11.4; 514/7.7 |
Current CPC
Class: |
C07K 16/241 20130101;
A61P 25/28 20180101; A61K 2039/54 20130101; A61K 38/1816 20130101;
A61K 38/49 20130101; A61K 38/27 20130101; A61K 38/215 20130101;
A61P 25/00 20180101; A61P 29/00 20180101 |
Class at
Publication: |
424/1.49 ;
424/142.1; 424/134.1; 424/130.1; 424/133.1; 514/1.1; 514/11.4;
424/94.64; 424/153.1; 514/7.7 |
International
Class: |
A61K 39/395 20060101
A61K039/395; A61K 38/27 20060101 A61K038/27; A61K 38/49 20060101
A61K038/49; A61P 29/00 20060101 A61P029/00; A61K 38/18 20060101
A61K038/18; A61K 51/10 20060101 A61K051/10; A61P 25/28 20060101
A61P025/28; A61P 25/00 20060101 A61P025/00; A61K 38/17 20060101
A61K038/17; A61K 38/48 20060101 A61K038/48 |
Claims
1. A method for delivering a biologic to a human with
Alzheimer's-related dementia, comprising administering said
biologic parenterally into the perispinal space of said human
without direct intrathecal injection, and thereafter positioning
said human's head below horizontal.
2. A method for delivering a TNF antagonist to the brain of a human
for treating mild cognitive impairment, Alzheimer's related
dementia, or vascular dementia, comprising administering the TNF
antagonist golimumab parenterally into the perispinal space of said
human without direct intrathecal injection, and thereafter
positioning said human in a Trendelenburg position, for delivery of
said golimumab to the brain via the human's vertebral venous
system.
3. A method for delivering a biologic to a human, comprising
administering said biologic parenterally into the perispinal space
of said human without direct intrathecal injection.
4. The method of claim 1, wherein said biologic is etanercept.
5. The method of claim 1, wherein said biologic is golimumab.
6. The method of claim 1, wherein said biologic is Gammagard.
7. The method of claim 1, wherein said biologic is
bapineuzumab.
8. The method of claim 2, further comprising positioning said
human's head below horizontal to facilitate gravity assisted
retrograde flow of golimumab to the brain.
9. The method of claim 3, wherein said human has neck pain.
10. The method of claim 3, wherein said human has cervical
radiculopathy.
11. The method of claim 3, wherein said human has degenerative disc
disease.
12. The method of claim 3, wherein said human has fibromyalgia.
13. The method of claim 3, wherein said human has neuropathic
pain.
14. The method of claim 3, wherein said human has sciatica.
15. The method of claim 3, wherein said human has low back
pain.
16. The method of claim 3, wherein the human has sciatica, and the
biologic is an anti-TNF-alpha therapeutic molecule.
17. The method of claim 3, wherein the human has sciatica, and the
biologic is etanercept.
18. The method of claim 3, wherein the biologic is etanercept.
19. The method of claim 1, wherein said administered biologic
bypasses the blood-brain barrier to reach the brain.
20. The method of claim 3, wherein said biologic is selected from
the group of etanercept, certolizumab pegol, IL-1 Trap,
Kineret.RTM., bevacizumab, pegaptanib, ranibizumab, rituximab,
Zevalin.RTM., Mylotarg.RTM., Campath.RTM., HumaSpect.RTM.,
abatacept, cetuximab, panitumumab, pegfilgrastim, filgrastim,
erythropoietin, Aranesp.RTM., trastuzumab, Pegasys.RTM., Intron
A.RTM., PEG-Intron.RTM., Infergen.RTM., Avonex.RTM., Rebif.RTM.,
Betaseron.RTM., Actimmune.RTM., Ontak.RTM., Simulect.RTM.,
Zenapax.RTM., Genkaxin.RTM., recombinant human growth hormone,
reteplase, alteplase, tPA (tissue plasminogen activator), urokinase
plasminogen activator, streptokinase, urokinase, or immune
globulin), Tarceva.RTM., bapineuzumab, Gammagard.TM., or IVIG.
Description
1. CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
12/568,661, filed Oct. 19, 2009, which is a continuation of
application Ser. No. 11/601,799, filed Nov. 17, 2006, now U.S. Pat.
No. 7,629,311, which is a continuation-in-part of application Ser.
No. 11/016,047, filed Dec. 18, 2004 now U.S. Pat. No. 7,214,658.
All of the above patents and patent applications included in this
paragraph are incorporated by reference in their entirety
herein.
[0002] This application is also related to provisional U.S. patent
application 60/662,744 entitled "Methods of Use of the Vertebral
Venous System to Deliver Biologics to the CNS" filed Mar. 16, 2005.
In addition to the above, this application claims priority from
U.S. provisional application 60/585,735, filed Jul. 6, 2004; U.S.
provisional application 60/738,331, entitled "Methods to facilitate
transmission of golimumab and other therapeutic molecules across
the blood-brain barrier", filed Nov. 18, 2005; and U.S. provisional
application entitled "Methods to facilitate transmission of
golimumab and other therapeutic molecules across the blood-brain,
blood-eye, and blood-nerve barriers", 60/760, 236, filed Jan. 18,
2006, all of which are hereby incorporated by reference in their
entirety herein. The use of perispinal administration of cytokine
antagonists to treat neurological disorders is discussed in US
patent application 20030049256 of this inventor. The use of
perispinal administration without direct intrathecal injection and
the vertebral venous system to deliver large molecules to the
brain, the eye, and the auditory apparatus are discussed in
provisional patent applications 60/585,735 filed Jul. 6, 2004;
60/659,414 filed Mar. 9, 2005; 60/662,744 filed Mar. 17, 2005; and
60/669,022, filed Apr. 7, 2005. All of the above patents and patent
applications included in this paragraph are incorporated by
reference in their entirety herein.
2. FIELD OF THE INVENTION
[0003] This application concerns novel methods which enable
golimumab, an anti-TNF biologic and other molecules, to cross the
blood-brain barrier, the blood-eye barrier, and/or the blood-nerve
barrier and therefore be of therapeutic use in humans and other
mammals. These methods involve perispinal administration of each of
these molecules without direct intrathecal injection. Perispinal
administration is defined as administration of the molecule into
the anatomic area within 10 cm of the spine. Perispinal
administration results in absorption of golimumab into the
vertebral venous system. The vertebral venous system is capable of
transporting molecules to the head, including into the brain, the
eye, the retina, the auditory apparatus, the cranial nerves or the
head, via retrograde venous flow, thereby bypassing the blood-brain
barrier and delivering the molecules to the brain, the eye, the
retina, the auditory apparatus, the cranial nerves or the head.
[0004] This method may be utilized for a wide variety of large
molecules, including, but not limited to, recombinant DNA
therapeutics, other biologics, monoclonal antibodies, fusion
proteins, monoclonal antibody fragments, hormones, cytokines,
anti-cytokines, interleukins, anti-interleukins, interferons,
colony-stimulating factors, cancer chemotherapeutic agents, growth
factors, anti-virals and antibiotics.
[0005] In addition the methods of the present invention may be used
to deliver molecules with a MW less than 2,000 daltons to the brain
and other structures of the head more efficiently than if delivered
systemically, and these methods utilizing these molecules are also
to be considered a part of this invention.
[0006] In addition to human use, these methods may be used to treat
other mammals, including horses, dogs, and cats.
[0007] This method may be used for delivery for humans or other
mammals with neurodegenerative diseases, including Alzheimer's
Disease and other forms of dementia, including both
Alzheimer's-related dementia and non-Alzheimer dementias;
Parkinson's Disease, amyotrophic lateral sclerosis; for eye
disorders or diseases including, but not limited to, macular
degeneration, diabetic retinopathy, sympathetic opthalmia and
retinitis pigmentosa; disorders of hearing, including, but not
limited to sensorineural hearing loss or presbycusis; central
nervous system (CNS) tumors, including tumors of the brain; for
other diseases or disorders of the brain, including, but not
limited to vascular disorders such as stroke, transient ischemic
attack, vascular dementia, and cerebrovascular disease; infectious
diseases of the CNS, including viral and bacterial infections; for
sciatica, cervical radiculopathy, and other forms of disc-related
pain; for low back pain; other diseases or disorders involving the
spine, the spinal cord, the spinal nerve roots, the brain, eyes,
auditory apparatus, or other structures of the head.
[0008] The use of cytokine antagonists to treat neurological
disorders is the subject of several previous patents of this
inventor, including U.S. Pat. Nos. 6,015,557, 6,177,077, 6,419,934
6,419,944, 6,423,321, 6,428,787, 6,537,549, 6,623,736 and US patent
applications 20030049256 and U.S. patent application Ser. No.
11/016,047, filed Dec. 18, 2004, entitled "Methods of use of
etanercept to improve human cognitive function", and provisional
U.S. patent application 60/585,735, filed Jul. 6, 2004. These
issued patents, patent applications, and provisional patent
applications are incorporated in their entirety herein. This
invention includes further applications of these ideas.
[0009] The adverse biologic effects of excess TNF can be reduced by
the use of biologic inhibitors of TNF. These inhibitors can be
divided into two broad categories: monoclonal antibodies and their
derivatives; and TNF binding biologics which are not antibody
based. In the first category belong golimumab, also known as
CNTO-148 (Centocor, Schering-Plough), infliximab (Remicade.RTM.,
Centocor), adalimumab (Humira.RTM., Abbott), and CDP 870
(Celltech). The second category includes etanercept, soluble TNF
receptor type 1, pegylated soluble TNF receptor type 1 (Amgen) and
onercept (Serono). Etanercept has a serum half life of
approximately 4.8 days when administered to patients with
rheumatoid arthritis on a chronic basis; onercept has a serum
half-life which is considerably shorter, and it is usually
administered at least three times weekly when used to treat
systemic illnesses.
[0010] Golimumab has many biologic effects. Golimumab, for example,
in addition to being a potent anti-inflammatory also has important
anti-apoptotic effects which may be of particular importance in
treating neurological disorders, such as certain forms of dementia,
where apoptosis plays a pathogenetic role.
[0011] Antibodies (immunoglobulins) are proteins produced by one
class of lymphocytes (B cells) in response to specific exogenous
foreign molecules (antigens). Monoclonal antibodies (mAB),
identical immunoglobulin copies which recognize a single antigen,
are derived from clones (identical copies) of a single B cell. This
technology enables large quantities of an immunoglobulin with a
specific target to be mass produced.
[0012] Monoclonal antibodies with a high affinity for a specific
cytokine will tend to reduce the biologic activity of that
cytokine. Substances which reduce the biologic effect of a cytokine
can be described in any of the following ways: as a cytokine
blocker; as a cytokine inhibitor; or as a cytokine antagonist. In
this patent, the terms blocker, inhibitor, and antagonist are used
interchangeably with respect to cytokines.
[0013] Advances in biotechnology have resulted in improved
molecules as compared to simply using monoclonal antibodies. One
such molecule is CDP 870 which, rather than being a monoclonal
antibody, is a new type of molecule, that being an antibody
fragment. By removing part of the antibody structure, the function
of this molecule is changed so that it acts differently in the
human body. Another new type of molecule, distinct from monoclonal
antibodies and soluble receptors, is a fusion protein. One such
example is etanercept. This molecule has a distinct function which
acts differently in the human body than a simple soluble receptor
or receptors.
[0014] Monoclonal antibodies, fusion proteins, and all of the
specific molecules discussed above under the categories of TNF
antagonists and interleukin antagonists are considered biologics,
in contrast to drugs that are chemically synthesized. For the
purpose of this patent a biologic is defined as a molecule produced
through recombinant DNA technology which is derived from the DNA of
a living source. The living sources may include humans, other
animals, or microorganisms. The biologics mentioned above are
manufactured using biotechnology, which usually involves the use of
recombinant DNA technology. Cytokine antagonists are one type of
biologic. Biologics are regulated through a specific division of
the FDA.
[0015] Cytokine antagonists can take several forms. They may be
monoclonal antibodies (defined above). They may be a monoclonal
antibody fragment. They may take the form of a soluble receptor to
that cytokine Soluble receptors freely circulate in the body. When
they encounter their target cytokine they bind to it, effectively
inactivating the cytokine, since the cytokine is then no longer
able to bind with its biologic target in the body. An even more
potent antagonist consists of two soluble receptors fused together
to a specific portion of an immunoglobulin molecule (Fc fragment).
This produces a dimer composed of two soluble receptors which have
a high affinity for the target, and a prolonged half-life. This new
molecule is called a fusion protein. An example of this new type of
molecule, called a fusion protein, is etanercept (Enbrel.RTM.).
[0016] TNF, a naturally occurring cytokine present in humans and
other mammals, plays a key role in the inflammatory response, in
the immune response and in the response to infection. TNF is formed
by the cleavage of a precursor transmembrane protein, forming
soluble molecules which aggregate in vivo to form trimolecular
complexes. These complexes then bind to receptors found on a
variety of cells. Binding produces an array of pro-inflammatory
effects, including release of other pro-inflammatory cytokines,
including IL-6, IL-8, and IL-1; release of matrix
metalloproteinases; and up regulation of the expression of
endothelial adhesion molecules, further amplifying the inflammatory
and immune cascade by attracting leukocytes into extravascular
tissues.
[0017] Golimumab is currently in clinical development by
Centocor/Schering-Plough for treatment of rheumatoid arthritis,
with potential applications for uveitis, asthma, and Crohn's
Disease. It may be described as a immunoglobulin G1, anti-(human
tumor necrosis factor .alpha.) (human monoclonal CNTO 148
.gamma.1-chain), disulfide with human monoclonal CNTO 148 K-chain),
dimer, and has CAS Registry number 476181-74-5. It is a fully human
anti-TNF monoclonal antibody.
[0018] Etanercept (Enbrel.RTM., Amgen/Immunex), golimumab,
infliximab (Remicade.RTM., Centocor), adalimumab (Humira.RTM.,
Abbott), CDP 870, and onercept are potent and selective inhibitors
of TNF. CDP 870, golimumab and onercept are in clinical
development. Etanercept, adalimumab, and infliximab are FDA
approved for chronic systemic use to treat rheumatoid arthritis and
certain other chronic inflammatory disorders. Golimumab has a
molecular weight of approximately 147,000 daltons.
[0019] Bevacizumab (Avastin.TM., Genentech) is a recombinant
humanized monoclonal IgG1 antibody that binds to and inhibits the
biologic activity of human vascular endothelial growth factor
(VEGF) and which may be useful for the treatment of various
malignancies. Bevacizumab has a molecular weight of 149,000 daltons
and is therefore too large to readily cross the blood-brain barrier
if administered systemically.
[0020] Anti-amyloid antibodies of the present invention include
immune globulin derived from human plasma, including Gammagard.TM.
and Kiovig.TM. brands of IVIG produced by Baxter and other brands
of IVIG; antibodies against beta-amyloid; and, specifically,
Bapineuzumab, a humanized monoclonal antibody to A-beta currently
being jointly developed by Elan and Wyeth.
[0021] Etanercept, one of the molecules of this invention, can also
be designated as TNFR:Fc because it is a dimeric fusion protein
consisting of two soluble TNF receptors fused to a Fc portion of an
immunoglobulin molecule. This fusion protein functions in a manner
quite distinct from a simple soluble TNF receptor. Soluble TNF
receptors are normally present in the human body. But the use of
these soluble TNF receptors as therapeutic agents for the treatment
of the conditions of consideration in this patent is made
impractical by their extremely short half-life and therefore their
limited biologic activity. The present invention utilizing
etanercept is therefore distinguished from an invention specifying
the use of a soluble TNF receptor. It is incorrect and imprecise to
describe etanercept as a soluble TNF receptor because this is an
incorrect description of its complex structure and omits
characteristics of etanercept which are absolutely essential to its
function. This is further underscored by the developmental history
of etanercept. In its first iteration the precursor molecule to
etanercept was produced with a single TNF receptor fused to an
immunoglobulin fragment. The biologic activity of this molecule was
poor. Therefore not only is etanercept distinguished from a soluble
TNF receptor, it is also distinguished from a TNF-binding fusion
protein which contains the recombinant DNA sequence of only a
single soluble TNF receptor. The unique structure of etanercept,
containing a dimer (two) soluble TNF receptors fused to an Fc
portion of an immunoglobulin molecule, is necessary for the proper
performance of the present invention. Since etanercept has the
molecular structure of a fusion protein it is thus quite distinct
from both onercept, soluble TNF receptor type 1 and pegylated
soluble TNF receptor type 1.
[0022] The vertebral venous system can also be used to deliver
other types of therapeutic agents to the cerebral cortex, eye,
retina, cerebellum, brainstem, eighth cranial nerve, cochlea, inner
ear, and cerebrospinal fluid. These therapeutic agents include
pharmacologic agents, other cytokine antagonists, and growth
factors which affect neuronal function, or the immune response
impacting neuronal function, including, but not limited to:
interleukins including IL-1, IL-2, IL-4, IL-6, IL-10, and IL-13;
interleukin 1 antagonists, such as IL-1 RA (Kineret.RTM., Amgen)
and IL-1 Trap; fusion proteins, such as IL-10 fusion protein and
etanercept (Enbrel.RTM., Immunex); human growth hormone and related
biologics (recombinant human growth hormone, Humatrope.RTM.
(somatropin) Eli Lilly & Co., Nutropin.RTM./Nutropin AQ.RTM.
(somatropin), Geref.RTM. (sermorelin) Serono, and Protropin.RTM.
(somatrem) Genentech)); BDNF; erythropoietin (Epogen.RTM. (epoetin
alpha) Amgen, Procrit.RTM. (epoetin alpha) Johnson & Johnson);
G-CSF (Neupogen.RTM. (filgrastim), Amgen); GM-CSF; Intron.RTM. A
(interferon alfa-2b) Schering-Plough; Avonex.RTM. (interferon
beta-1a) Biogen; bevacizumab (Avastin.TM., Genentech); pegaptanib,
ranibizumab, and other biologic VEGF antagonists; alefacept
(LFA-3/IgG1 human fusion protein, Amevive.RTM. Biogen); Epidermal
growth factor; anti-EGF (ABX-EGF, Abgenix); transforming growth
factor-beta 1 (TGF-beta 1); NGF, or other compounds with CNS,
vascular or immune therapeutic activity. Perispinal delivery is
particularly advantageous when biologics, such as etanercept, which
profoundly affect neuronal function, are administered because of
their efficacy at extremely low concentration (high biologic
potency).
[0023] This method may be used for delivery for humans or other
mammals with neurodegenerative diseases, including Alzheimer's
Disease, other forms of Alzheimer-related dementia, non-Alzheimer
dementia, Parkinson's Disease, and amyotrophic lateral sclerosis;
for eye disorders or diseases including, but not limited to,
macular degeneration, diabetic retinopathy, sympathetic opthalmia
and retinitis pigmentosa; disorders of hearing, including, but not
limited to sensorineural hearing loss or presbycusis; central
nervous system (CNS) tumors, including tumors of the brain; for
other diseases or disorders of the brain, including, but not
limited to vascular disorders such as stroke, transient ischemic
attack, vascular dementia, and cerebrovascular disease; infectious
diseases of the CNS, including viral and bacterial infections; for
sciatica, cervical radiculopathy, and other forms of disc-related
pain; for low back pain; other diseases or disorders involving the
spine, the spinal cord, the spinal nerve roots, the brain, eyes,
auditory apparatus, or other structures of the head.
3. BACKGROUND OF THE INVENTION
[0024] The following description of the background of the invention
is provided as an aid to understanding the invention and is not
admitted to describe or constitute prior art to the invention.
[0025] This application concerns novel methods which enable
golimumab, an anti-TNF biologic and other molecules, to cross the
blood-brain barrier, the blood-eye barrier, and/or the blood-nerve
barrier and therefore be of therapeutic use in humans and other
mammals. Included among these methods are those which involve
perispinal administration of golimumab without direct intrathecal
injection. In addition, additional methods involve the perispinal
administration of other molecules, as detailed herein. Perispinal
administration is defined as administration of the molecule into
the anatomic area within 10 cm of the spine. Perispinal
administration results in absorption of golimumab or other
molecules given by perispinal administration, into the vertebral
venous system. The vertebral venous system is capable of
transporting therapeutic molecules to the head, including into the
brain, the eye, the retina, the auditory apparatus, the cranial
nerves or the head, via retrograde venous flow, thereby bypassing
the blood-brain barrier and delivering the molecules to the brain,
the eye, the retina, the auditory apparatus, the cranial nerves or
the head.
[0026] This method may be utilized for a wide variety of large
molecules, including, but not limited to, recombinant DNA
therapeutics, other biologics, monoclonal antibodies, fusion
proteins, monoclonal antibody fragments, hormones, cytokines,
anti-cytokines, interleukins, anti-interleukins, interferons,
colony-stimulating factors, cancer chemotherapeutic agents, growth
factors, anti-virals and antibiotics.
[0027] In addition the methods of the present invention may be used
to deliver molecules with a MW less than 2,000 daltons to the brain
and other structures of the head more efficiently than if delivered
systemically, and these methods utilizing these smaller molecules
are also to be considered a part of this invention.
[0028] In addition to human use, these methods may be used to treat
other mammals, including horses, dogs, and cats.
[0029] This method may be used for delivery for humans or other
mammals with neurodegenerative diseases, including Alzheimer's
Disease, Parkinson's Disease, amyotrophic lateral sclerosis; for
eye disorders or diseases including, but not limited to, macular
degeneration, diabetic retinopathy, sympathetic opthalmia and
retinitis pigmentosa; disorders of hearing, including, but not
limited to sensorineural hearing loss or presbycusis; central
nervous system (CNS) tumors, including tumors of the brain; for
other diseases or disorders of the brain, including, but not
limited to vascular disorders such as stroke, transient ischemic
attack, vascular dementia, and cerebrovascular disease; infectious
diseases of the CNS, including viral and bacterial infections; for
sciatica, cervical radiculopathy, and other forms of disc-related
pain; for low back pain; other diseases or disorders involving the
spine, the spinal cord, the spinal nerve roots, the brain, eyes,
auditory apparatus, or other structures of the head.
[0030] The use of cytokine antagonists to treat neurological
disorders is the subject of several previous patents of this
inventor, including U.S. Pat. Nos. 6,015,557, 6,177,077, 6,419,934
6,419,944, 6,423,321, 6,428,787, 6,537,549, 6,623,736 and US patent
applications 20030049256 and U.S. patent application Ser. No.
11/016,047, filed Dec. 18, 2004, entitled "Methods of use of
etanercept to improve human cognitive function", and provisional
U.S. patent application 60/585,735, filed Jul. 6, 2004. These
issued patents, patent applications, and provisional patent
applications are incorporated in their entirety herein. This
invention includes further applications of these ideas.
[0031] The adverse biologic effects of excess TNF can be reduced by
the use of biologic inhibitors of TNF. These inhibitors can be
divided into two broad categories: monoclonal antibodies and their
derivatives; and TNF binding biologics which are not antibody
based. In the first category belong golimumab, also known as
CNTO-148 (Centocor, Schering-Plough), infliximab (Remicade.RTM.,
Centocor), adalimumab (Humira.RTM., Abbott), and CDP 870
(Celltech). The second category includes etanercept, soluble TNF
receptor type 1, pegylated soluble TNF receptor type 1 (Amgen) and
onercept (Serono). Etanercept has a serum half life of
approximately 4.8 days when administered to patients with
rheumatoid arthritis on a chronic basis; onercept has a serum
half-life which is considerably shorter, and it is usually
administered at least three times weekly when used to treat
systemic illnesses.
[0032] Golimumab has many biologic effects. Golimumab, for example,
in addition to being a potent anti-inflammatory also has important
anti-apoptotic effects which may be of particular importance in
treating neurological disorders, such as certain forms of dementia,
where apoptosis plays a pathogenetic role.
[0033] Antibodies (immunoglobulins) are proteins produced by one
class of lymphocytes (B cells) in response to specific exogenous
foreign molecules (antigens). Monoclonal antibodies (mAB),
identical immunoglobulin copies which recognize a single antigen,
are derived from clones (identical copies) of a single B cell. This
technology enables large quantities of an immunoglobulin with a
specific target to be mass produced.
[0034] Monoclonal antibodies with a high affinity for a specific
cytokine will tend to reduce the biologic activity of that cytokine
Substances which reduce the biologic effect of a cytokine can be
described in any of the following ways: as a cytokine blocker; as a
cytokine inhibitor; or as a cytokine antagonist. In this patent,
the terms blocker, inhibitor, and antagonist are used
interchangeably with respect to cytokines.
[0035] Advances in biotechnology have resulted in improved
molecules as compared to simply using monoclonal antibodies. One
such molecule is CDP 870 which, rather than being a monoclonal
antibody, is a new type of molecule, that being an antibody
fragment. By removing part of the antibody structure, the function
of this molecule is changed so that it acts differently in the
human body. Another new type of molecule, distinct from monoclonal
antibodies and soluble receptors, is a fusion protein. One such
example is etanercept. This molecule has a distinct function which
acts differently in the human body than a simple soluble receptor
or receptors.
[0036] Monoclonal antibodies, fusion proteins, and all of the
specific molecules discussed above under the categories of TNF
antagonists and interleukin antagonists are considered biologics,
in contrast to drugs that are chemically synthesized. For the
purpose of this patent a biologic is defined as a molecule produced
through recombinant DNA technology which is derived from the DNA of
a living source. The living sources may include humans, other
animals, or microorganisms. The biologics mentioned above are
manufactured using biotechnology, which usually involves the use of
recombinant DNA technology. Cytokine antagonists are one type of
biologic. Biologics are regulated through a specific division of
the FDA.
[0037] Cytokine antagonists can take several forms. They may be
monoclonal antibodies (defined above). They may be a monoclonal
antibody fragment. They may take the form of a soluble receptor to
that cytokine Soluble receptors freely circulate in the body. When
they encounter their target cytokine they bind to it, effectively
inactivating the cytokine, since the cytokine is then no longer
able to bind with its biologic target in the body. An even more
potent antagonist consists of two soluble receptors fused together
to a specific portion of an immunoglobulin molecule (Fc fragment).
This produces a dimer composed of two soluble receptors which have
a high affinity for the target, and a prolonged half-life. This new
molecule is called a fusion protein. An example of this new type of
molecule, called a fusion protein, is etanercept (Enbrel.RTM.).
[0038] TNF, a naturally occurring cytokine present in humans and
other mammals, plays a key role in the inflammatory response, in
the immune response and in the response to infection. TNF is formed
by the cleavage of a precursor transmembrane protein, forming
soluble molecules which aggregate in vivo to form trimolecular
complexes. These complexes then bind to receptors found on a
variety of cells. Binding produces an array of pro-inflammatory
effects, including release of other pro-inflammatory cytokines,
including IL-6, IL-8, and IL-1; release of matrix
metalloproteinases; and up regulation of the expression of
endothelial adhesion molecules, further amplifying the inflammatory
and immune cascade by attracting leukocytes into extravascular
tissues.
[0039] Golimumab is currently in clinical development by
Centocor/Schering-Plough for treatment of rheumatoid arthritis,
with potential applications for uveitis, asthma, and Crohn's
Disease. It may be described as a immunoglobulin G1, anti-(human
tumor necrosis factor .alpha.) (human monoclonal CNTO 148
.gamma.1-chain), disulfide with human monoclonal CNTO 148 K-chain),
dimer, and has CAS Registry number 476181-74-5. It is a fully human
anti-TNF monoclonal antibody.
[0040] Etanercept (Enbrel.RTM., Amgen/Immunex), golimumab,
infliximab (Remicade.RTM., Centocor), adalimumab (Humira.RTM.,
Abbott), CDP 870, and onercept are potent and selective inhibitors
of TNF. CDP 870, golimumab and onercept are in clinical
development. Etanercept, adalimumab, and infliximab are FDA
approved for chronic systemic use to treat rheumatoid arthritis and
certain other chronic inflammatory disorders. Golimumab has a
molecular weight of approximately 147,000 daltons.
[0041] Bevacizumab (Avastin.TM., Genentech) is a recombinant
humanized monoclonal IgG1 antibody that binds to and inhibits the
biologic activity of human vascular endothelial growth factor
(VEGF) and which may be useful for the treatment of various
malignancies. Bevacizumab has a molecular weight of 149,000 daltons
and is therefore too large to readily cross the blood-brain barrier
if administered systemically.
[0042] Etanercept can also be designated as TNFR:Fc because it is a
dimeric fusion protein consisting of two soluble TNF receptors
fused to a Fc portion of an immunoglobulin molecule. This fusion
protein functions in a manner quite distinct from a simple soluble
TNF receptor. Soluble TNF receptors are normally present in the
human body. But the use of these soluble TNF receptors as
therapeutic agents for the treatment of the conditions of
consideration in this patent is made impractical by their extremely
short half-life and therefore their limited biologic activity. The
present invention utilizing etanercept is therefore distinguished
from an invention specifying the use of a soluble TNF receptor. It
is incorrect and imprecise to describe etanercept as a soluble TNF
receptor because this is an incorrect description of its complex
structure and omits characteristics of etanercept which are
absolutely essential to its function. This is further underscored
by the developmental history of etanercept. In its first iteration
the precursor molecule to etanercept was produced with a single TNF
receptor fused to an immunoglobulin fragment. The biologic activity
of this molecule was poor. Therefore not only is etanercept
distinguished from a soluble TNF receptor, it is also distinguished
from a TNF-binding fusion protein which contains the recombinant
DNA sequence of only a single soluble TNF receptor. The unique
structure of etanercept, containing a dimer (two) soluble TNF
receptors fused to an Fc portion of an immunoglobulin molecule, is
necessary for the proper performance of the present invention.
Since etanercept has the molecular structure of a fusion protein it
is thus quite distinct from both onercept, soluble TNF receptor
type 1 and pegylated soluble TNF receptor type 1.
[0043] The vertebral venous system can also be used to deliver
other types of therapeutic agents to the cerebral cortex, eye,
retina, cerebellum, brainstem, eighth cranial nerve, cochlea, inner
ear, and cerebrospinal fluid. These therapeutic agents include
pharmacologic agents, other cytokine antagonists, and growth
factors which affect neuronal function, or the immune response
impacting neuronal function, including, but not limited to:
interleukins including IL-1, IL-2, IL-4, IL-6, IL-10, and IL-13;
interleukin 1 antagonists, such as IL-1 RA (Kineret.RTM., Amgen)
and IL-1 Trap; fusion proteins, such as IL-10 fusion protein and
etanercept (Enbrel.RTM., Immunex); human growth hormone and related
biologics (recombinant human growth hormone, Humatrope.RTM.
(somatropin) Eli Lilly & Co., Nutropin.RTM./Nutropin AQ.RTM.
(somatropin), Geref.RTM. (sermorelin) Serono, and Protropin.RTM.
(somatrem) Genentech)); BDNF; erythropoietin (Epogen.RTM. (epoetin
alpha) Amgen, Procrit.RTM. (epoetin alpha) Johnson & Johnson);
G-CSF (Neupogen.RTM. (filgrastim), Amgen); GM-CSF; Intron.RTM. A
(interferon alfa-2b) Schering-Plough; Avonex.RTM. (interferon
beta-1a) Biogen; bevacizumab (Avastin.TM., Genentech); pegaptanib,
ranibizumab, and other biologic VEGF antagonists; alefacept
(LFA-3/IgG1 human fusion protein, Amevive.RTM. Biogen); Epidermal
growth factor; anti-EGF (ABX-EGF, Abgenix); transforming growth
factor-beta 1 (TGF-beta 1); NGF, or other compounds with CNS,
vascular or immune therapeutic activity. Perispinal delivery is
particularly advantageous when biologics, such as etanercept, which
profoundly affect neuronal function, are administered because of
their efficacy at extremely low concentration (high biologic
potency).
[0044] This method may be used for delivery for humans or other
mammals with neurodegenerative diseases, including Alzheimer's
Disease, Parkinson's Disease, amyotrophic lateral sclerosis; for
eye disorders or diseases including, but not limited to, macular
degeneration, diabetic retinopathy, sympathetic opthalmia and
retinitis pigmentosa; disorders of hearing, including, but not
limited to sensorineural hearing loss or presbycusis; central
nervous system (CNS) tumors, including tumors of the brain; for
other diseases or disorders of the brain, including, but not
limited to vascular disorders such as stroke, transient ischemic
attack, vascular dementia, and cerebrovascular disease; infectious
diseases of the CNS, including viral and bacterial infections; for
sciatica, cervical radiculopathy, and other forms of disc-related
pain; for low back pain; other diseases or disorders involving the
spine, the spinal cord, the spinal nerve roots, the brain, eyes,
auditory apparatus, or other structures of the head.
[0045] Localized administration for the treatment of localized
clinical disorders has many clinical advantages over the use of
conventional systemic treatment. Locally administered medication
after delivery diffuses through local capillary, venous, arterial,
and lymphatic action to reach the therapeutic target. In addition
local administration of a large molecule, such as goliumumab,
defined as a molecule with a molecular weight greater than or equal
to 2,000 daltons, in the vicinity of the spine (perispinal
administration) without direct intrathecal injection has the key
advantage of improved delivery of the molecule to the brain and
across the blood-brain barrier (BBB), with delivery enhanced by
transport via the vertebral venous system. Intrathecal injection
delivers the molecule into the cerebrospinal fluid (CSF), but has
disadvantages of possible infection, hemorrhage, and subsequent CSF
leak.
[0046] The BBB is a physiologic barrier which separates the brain
and cerebrospinal fluid from the blood. It consists of a layer of
cells which comprise the cerebral capillary endothelium, the
choroid plexus epithelium, and the arachnoid membranes, which are
connected by tight junctions (zonulae occludens). These tight
junctions may be as much as 100 times tighter than junctions of
other capillary endothelium, and prevent molecules larger than
about 600 daltons in molecular weight (MW) from traversing the BBB
when the molecule is administered systemically i.e. by conventional
subcutaneous, intramuscular, or intravenous injection at an
anatomic site remote from the spine.
[0047] The vertebral venous system (VVS) is an interconnected
plexus of veins which surrounds the spinal cord and extends the
entire length of the spine. This venous system provides a vascular
route from the pelvis to the cranium which richly involves the bone
marrow of the spine and which is functionally distinct from the
systemic venous system. First described by Willis in 1663, the
functional significance of the vertebral venous system was largely
unappreciated until the work of Batson, who in 1940 proposed that
this venous plexus provided the route by which prostate cancer
metastasizes to the vertebral column. Acceptance of Batson's
proposal by the medical community has led to the designation of the
vertebral venous system as Batson's Plexus. Although now widely
appreciated as a possible route by which cancer cells may spread to
the spine there have been no previous suggestions that Batson's
plexus may be of therapeutic usefulness. The use of Batson's plexus
as route of delivery of biologics for clinical use, and as a route
for delivery of large molecules to the brain, the eye, the retina,
the auditory apparatus, the cranial nerves or the head are
inventions of the author. This patent is a continuation to the
methods of use of Batson's plexus to deliver therapeutic molecules
to the nervous system which has been previously proposed by the
inventor, and incorporates the previous patents and patent
applications discussing this. In addition this patent is related to
provisional U.S. patent application 60/662,744 entitled "Methods of
Use of the Vertebral Venous System to Deliver Biologics to the CNS"
filed Mar. 16, 2005, and application Ser. No. 10/269,745, entitled
"Cytokine antagonists for neurological and neuropsychiatric
disorders", filed Oct. 9, 2002, and each of these patent
applications are hereby incorporated herein in their entirety.
[0048] Perispinal administration involves anatomically localized
delivery performed so as to place the therapeutic molecule directly
in the vicinity of the spine at the time of initial administration.
For the purposes of this patent, "in the vicinity of" is defined as
within 10 centimeters. Perispinal administration includes, but is
not limited to, the following types of administration: parenteral;
subcutaneous; intramuscular; or interspinous; and specifically
includes the use of interspinous injection carried through the skin
in the midline of the neck or back, directly overlying the spine.
For the purposes of this patent perispinal administration excludes
intrathecal administration, which carries additional risks of
infection and hemorrhage. Therefore in this patent "perispinal" is
more exactly defined as "perispinal (extrathecal)", but for the
purposes of brevity shall be designated throughout simply as
"perispinal". Perispinal administration leads to enhanced delivery
of large molecules to the brain and the head and the structures
therein in a therapeutically effective amount. The conventional
mode of delivery of these molecules for clinical applications, i.e.
subcutaneous administration in the abdomen, thighs, or arms, does
not effectuate delivery across the blood-brain barrier (see
Robinson reference 60) which is as efficient as perispinal
administration and is therefore distinguished from the perispinal
methods of administration described in this invention.
[0049] Hearing loss occurs in humans in many forms. Hearing is
essential to the normal conduct of one's daily activities and
people with impaired hearing have many difficulties. Hearing loss
can date from birth; it can be acquired later in life; or it can be
the result of trauma, accident, disease, or a toxic effect of a
medication. It can be genetic, either as a solitary disorder or as
part of a complex syndrome. Hearing loss is one of the most common
chronic neurological impairments, estimated to affect about 4
percent of those under 45 in the United States, and about 29
percent of those 65 years or older.
[0050] As defined herein, the auditory apparatus includes the
cochlea, the auditory division of the eighth cranial nerve, and the
central auditory pathways. Sensorineural hearing loss is one
particular category of hearing loss and is caused by lesions of the
cochlea and/or the auditory division of the eighth cranial nerve.
Prior to this invention, treatment of this condition was primarily
limited to the use of hearing aids.
[0051] The pathogenetic mechanism of most forms of hearing loss has
yet to be fully defined. Hearing loss can be due to conductive
problems, which is not the subject of this patent; central hearing
loss due to lesions of the central auditory pathway; or
sensorineural hearing loss.
[0052] Humans react to sounds that are transduced into neurally
conducted impulses through the action of neuroepithelial cells
(hair cells) and spiral ganglion cells (neurons) in the inner ear.
These impulses are transmitted along the cochlear division of the
eighth cranial nerve into the brainstem and the central auditory
pathways.
[0053] Presbycusis, or age-related hearing loss, is a type of
sensorineural deafness which affects one-third of the population
over the age of 75. The exact mechanism of presbycusis is unknown,
and has long been thought to be multifactorial. Inflammation has
not previously been thought to be a significant factor in the
pathogenesis of presbycusis. Yet a previous study did suggest that
genes encoded by the major histocompatibility complex (MHC) had a
role in certain hearing disorders. (Bernstein, Acta Otolaryngol
1996 September; 116(5):666-71). The MHC is known to be central to
the immune response and inflammation.
[0054] As will be discussed below there is now clinical evidence
that inflammation has a role in the pathogenesis of various types
of sensorineural hearing loss, including presbycusis. This opens up
a new avenue of treatment of these disorders utilizing large
molecules delivered by perispinal administration without direct
intrathecal injection, including biologic TNF inhibitors and other
large molecules with a molecular weight equal to or greater than
2,000 daltons.
[0055] As discussed in the previous patents and patent applications
of the inventor, including U.S. Pat. Nos. 6,082,089; 6,537,549, and
the others as enumerated above, including those detailed in section
1 of this application, the methods of the present invention may be
utilized to treat sciatica, cervical radiculopathy, fibromyalgia,
severe low back pain and/or related pain conditions, including
neuropathic pain.
4. DESCRIPTION OF THE PRIOR ART
[0056] Pharmacologic chemical substances, compounds and agents
having various organic structures and metabolic functions which are
used for the treatment of sensorineural hearing loss, and TNF
related diseases have been disclosed in the prior art. One example
is U.S. Pat. No. 5,837,681, entitled "Method For Treating
Sensorineural Hearing Loss Using Glial Cell Line-Derived
Neurotrophic Factor (GDNF) Protein Product". However, this prior
art patent does not teach the use of a TNF antagonist delivered via
the vertebral venous system, as in the present invention, and GDNF
has biologic actions which are clearly distinct from those of the
TNF binding biologics of the present invention.
[0057] U.S. Pat. No. 6,043,221 entitled "Method For Preventing And
Treating Hearing Loss Using A Neuturin Protein Product" discusses
the use of a neurotrophic factor. This prior art patent does not
teach the use of a TNF antagonist delivered via the vertebral
venous system to treat disorders of the brain, as in the present
invention.
[0058] U.S. Pat. No. 5,385,901 entitled "Method Of Treating
Abnormal Concentrations of TNF Alpha" discloses a method for the
use of TNF antagonists. This prior art patent does not teach the
use of a biologic delivered via the vertebral venous system as
described in the present invention for the suppression and
inhibition of the action of TNF in the human body to treat
disorders of the brain, as in the present invention.
[0059] U.S. Pat. No. 5,434,170 entitled "Method For Treating
Neurocognitive Disorders" discloses the use of thalidomide to treat
dementia. This prior art patent does not teach the use of
etanercept or another biologic delivered via the vertebral venous
system as described in the present invention to treat disorders of
the brain.
[0060] U.S. Pat. No. 6,277,969 discloses the use of anti-TNF
antibodies for treatment of various disorders. This prior art
patent does not teach the use of etanercept or another biologic
delivered via the vertebral venous system as described in the
present invention to treat disorders of the brain.
[0061] U.S. Patent application 2004/0258671 by Watkins entitled
"Methods for Treating Pain" discloses the use of IL-10 and IL-10
fusion protein and other biologics for treating pain. This patient
application does not disclose the use of these substances to treat
disorders of the brain.
[0062] U.S. Pat. No. 5,656,272 to LE et. al. discloses the use of
TNF inhibitors for treatment of various disorders, including the
use of anti-TNF monoclonal antibodies. This prior art patent does
not teach the use of etanercept or another biologic delivered via
the vertebral venous system as described in the present invention
to treat disorders of the brain.
[0063] U.S. Pat. No. 5,650,396 discloses a method of treating
multiple sclerosis (MS) by blocking and inhibiting the action of
TNF in a patient. This prior art patent does not teach the use of
etanercept or another biologic delivered via the vertebral venous
system as described in the present invention to treat disorders of
the brain.
[0064] U.S. Pat. No. 5,605,690 discloses the use of TNF inhibitors
for treatment of various disorders. This prior art patent does not
teach the use of etanercept or another biologic delivered via the
vertebral venous system as described in the present invention to
treat disorders of the brain.
[0065] U.S. patent application US 2003/0148955 to Pluenneke
discloses the use of biologic TNF inhibitors, including etanercept,
for the treatment of medical disorders. However, it does not give
an enabling disclosure of the use of etanercept for the treatment
of disorders of the brain utilizing the vertebral venous system as
does the present invention and it does not predate the U.S. Pat.
No. 6,015,557 of the present inventor of which this patent
application is a continuation-in-part.
[0066] U.S. Pat. Nos. 7,115,557, 6,649,589 and 6,635,250 and
related patent applications which have not been granted, to
Olmarker and Rydevik, and previous publications by Olmarker (see
References) discuss the use of TNF inhibitors for the treatment of
nerve root injury and related disorders. These patents do not teach
the use of etanercept or another biologic delivered via the
vertebral venous system as described in the present invention to
treat disorders of the brain, and are not enabling with respect to
etanercept, golimumab, certolizumab pegol, and other molecules
discussed herein.
[0067] U.S. Pat. No. 5,863,769 discloses using IL-1 RA for treating
various diseases. This prior art patent does not teach the use of
an interleukin antagonist or other biologic delivered via the
vertebral venous system as described in the present invention to
treat disorders of the brain.
[0068] U.S. Pat. No. 6,013,253 discloses using interferon and IL-1
RA for treating multiple sclerosis. This prior art patent does not
teach the use of an interleukin antagonist or other biologic
delivered via the vertebral venous system as described in the
present invention to treat disorders of the brain.
[0069] U.S. Pat. No. 5,075,222 discloses the use of IL-1 inhibitors
for treatment of various disorders. This prior art patent does not
teach the use of an interleukin antagonist or other biologic
delivered via the vertebral venous system as described in the
present invention to treat disorders of the brain.
[0070] U.S. Pat. No. 6,159,460 discloses the use of IL-1 inhibitors
for treatment of various disorders. This prior art patent does not
teach the use of an interleukin antagonist or other biologic
delivered via the vertebral venous system as described in the
present invention to treat disorders of the brain.
[0071] U.S. Pat. No. 6,096,728 discloses the use of IL-1 inhibitors
for treatment of various disorders. This prior art patent does not
teach the use of an interleukin antagonist or other biologic
delivered via the vertebral venous system as described in the
present invention to treat disorders of the brain.
[0072] U.S. Pat. No. 6,548,527 to Rahman discloses the use of
etanercept for the treatment of immune mediated ear disorders. This
prior art patent does not teach the use of etanercept or other
biologic delivered via the vertebral venous system as described in
the present invention to treat disorders of the brain.
[0073] US patent application 20040072885 to Rahman discloses the
use of etanercept for the treatment of immune mediated ear
disorders. This prior art patent does not teach the use of an
etanercept or other biologic delivered via the vertebral venous
system as described in the present invention to treat disorders of
the brain.
[0074] An article (Rahman M U, Poe D S, Choi H K. Etanercept
therapy for immune-mediated cochleovestibular disorders:
preliminary results in a pilot study. Otol Neurotol. 2001
September; 22(5):619-24.) disclosed the use of etanercept by
subcutaneous administration for the treatment of immune mediated
ear disorders. This prior art patent does not teach the use of
etanercept or other biologic delivered via the vertebral venous
system as described in the present invention to treat disorders of
the brain.
[0075] Clemens (reference 57) demonstrated that the internal and
external vertebral venous plexuses freely intercommunicate, and
this was also demonstrated by Vogelsang (reference 58) with the use
of intraosseous spinal venography. But neither Clemens nor
Vogelsang discussed the use of the VVS to facilitate delivery of
large molecules to the brain, nor did they discuss the use of the
VVS for therapeutic purposes.
[0076] Groen (reference 50) confirmed the fact that all three
divisions of the vertebral venous system (internal and external
plexuses, and the basivertebral veins) freely intercommunicated,
and that all divisions of this system lacked valves. But Groen did
not discuss the use of the VVS to facilitate delivery of large
molecules to the brain, nor did he discuss the use of the VVS for
therapeutic purposes.
[0077] Two recent articles (Lirk references 54 and 55) discuss an
anatomic finding, disclosing the existence of a gap in a
ligamentous barrier to the epidural space. These articles, however,
do not discuss the administration of large molecules by the
perispinal route, or the relevance of this anatomic finding to the
delivery of large molecules to the brain.
[0078] Batson in 1940 (reference 47) published information
regarding the vertebral venous system. Experimentally he
demonstrated a connection between the pelvic venous system and the
vertebral venous system, and proposed that this was a route whereby
carcinoma originating in the pelvis could metastasize to the spine.
His work did not propose the use of the VVS for therapeutic
purposes, nor did it discuss or imply this possibility. His work
did not disclose the methods of the present invention for delivery
of large molecules to the brain.
[0079] Ruiz and Gisolf (references 44 and 45) have recently
published articles discussing the vertebral venous system and its
connections to the cranial venous system. Neither authors discuss
the potential use of this system as a route of administration of
large molecules to the brain.
[0080] Retrograde cerebral perfusion has been previously
demonstrated to deliver dye to the surface of the brain in pigs
after superior vena caval injection (Ye reference 42)) but the
authors did not propose the use of this route to deliver large
molecules to the brain.
[0081] Several authors (references 44-50) have discussed the
anatomy and function of the vertebral venous system but none have
proposed the use of the vertebral venous system as a route of
delivery of large molecules to the brain, nor have they proposed
the methods of the present invention.
[0082] Two articles by Byrod discussed a mechanism whereby
substances applied epidurally can cross into the endoneurial space
(Byrod references 51 and 52), but neither article discusses the
perispinal use of a large molecule for delivery to the brain.
[0083] Robinson (reference 60) states the prevailing view that
systemic administration of etanercept does not lead to therapeutic
concentrations of etanercept in the brain, because systemically
administered etanercept does not cross the BBB.
[0084] Markomichelakis (reference 62) in 2005, following the
issuance of U.S. Pat. No. 6,428,787 by this inventor which claimed
the use of infliximab to treat macular degeneration, described the
regression of macular degeneration following infliximab treatment
given systemically. This reference did not describe or discuss the
use of perispinal infliximab.
[0085] Olmarker has filed patent applications regarding the use of
anti-TNF molecules for treatment of spinal disorders, including
US20010027175, 20010055594, 20030176332, 20050220791, 20010027199,
and 20030039651, which have led to U.S. Pat. Nos. 6,635,250,
6,649,589, and 7115557. None of these applications or patents are
enabling for the use of perispinal etanercept or perispinal
golimumab for the applications discussed in the present
invention.
[0086] None of the prior art patents disclose or teach the use of
perispinal administration of large molecules as in the present
invention as a way of delivering large molecules to the brain, the
eyes, or the head, in which this method of administration provides
the patient with a better opportunity to heal, slows disease
progression, treats infection or otherwise improves the patient's
health.
[0087] None of the prior art patents disclose or teach the use of
perispinal administration of golimumab as in the present invention
as a way of delivering golimumab to the brain, the eyes, or the
head, in which this method of administration provides the patient
with a better opportunity to heal, slows disease progression,
treats infection or otherwise improves the patient's health.
[0088] In addition the prior art does not contain a description of
the methods of the current invention to deliver molecules smaller
than 2,000 daltons MW to the brain and other structures of the
head.
[0089] Accordingly, it is an object of the present invention to
provide golimumab administered through the perispinal route as a
new method of golimumab so that the use of golimumab will improve a
patient's health.
[0090] Another object of the present invention is to provide a
method to deliver golimumab across the blood-brain barrier so that
it is delivered to the brain in a therapeutically effective dose
and thereby treats a disease or disorder of the brain.
[0091] Another object of the present invention is to provide a
method to deliver golimumab across the blood-eye barrier so that it
is delivered to the eye in a therapeutically effective dose and
thereby treats a disease or disorder of the eye.
[0092] Another object of the present invention is to provide a
method to deliver golimumab across the blood-eye barrier so that it
is delivered to the retina in a therapeutically effective dose and
thereby treats a disease or disorder of the retina.
[0093] Another object of the present invention is to provide a
method to deliver golimumab across the blood-eye barrier so that it
is delivered to the retina in a therapeutically effective dose and
thereby treats macular degeneration.
[0094] Another object of the present invention is to provide a
method to deliver golimumab across the blood-eye barrier so that it
is delivered to the retina in a therapeutically effective dose and
thereby treats a disease or disorder of the diabetic
retinopathy.
[0095] Another object of the present invention is to provide a
method to deliver golimumab across the blood-brain barrier so that
it is delivered to the auditory apparatus in a therapeutically
effective dose and thereby treats a disease or disorder of the
auditory apparatus.
[0096] Another object of the present invention is to provide a
method to deliver golimumab across the blood-brain barrier so that
it is delivered to the brain in a therapeutically effective dose
and thereby treats dementia.
[0097] Another object of the present invention is to provide a
method to deliver golimumab across the blood-brain barrier so that
it is delivered to the brain in a therapeutically effective dose
and thereby treats a brain tumor.
[0098] Another object of the present invention is to provide a
method to deliver golimumab across the dural barrier so that it is
delivered to the spine in a therapeutically effective dose and
thereby treats a malignant tumor metastatic to the spine.
[0099] Another object of the present invention is to provide a
method to deliver golimumab across the dural barrier so that it is
delivered to the spinal nerve roots, the spinal cord, the dorsal
root ganglia, or the spine in a therapeutically effective dose and
thereby treats a spinal disorder, including sciatica, degenerative
disc disease, cervical radiculopathy, low back pain, or related
conditions.
[0100] Accordingly, it is an object of the present invention to
provide large molecules administered through the perispinal route
as a new method of use of such molecules so that the use of these
molecules will improve a patient's health.
[0101] Another object of the present invention is to provide a
method to deliver a large molecule across the blood-brain barrier
so that it is delivered to the brain in a therapeutically effective
dose and thereby treats a disease or disorder of the brain.
[0102] Another object of the present invention is to provide a
method to deliver a large molecule across the blood-eye barrier so
that it is delivered to the eye in a therapeutically effective dose
and thereby treats a disease or disorder of the eye.
[0103] Another object of the present invention is to provide a
method to deliver a large molecule across the blood-eye barrier so
that it is delivered to the retina in a therapeutically effective
dose and thereby treats a disease or disorder of the retina.
[0104] Another object of the present invention is to provide a
method to deliver a large molecule across the blood-eye barrier so
that it is delivered to the retina in a therapeutically effective
dose and thereby treats macular degeneration.
[0105] Another object of the present invention is to provide a
method to deliver a large molecule across the blood-eye barrier so
that it is delivered to the retina in a therapeutically effective
dose and thereby treats a disease or disorder of the diabetic
retinopathy.
[0106] Another object of the present invention is to provide a
method to deliver a large molecule across the blood-brain barrier
so that it is delivered to the auditory apparatus in a
therapeutically effective dose and thereby treats a disease or
disorder of the auditory apparatus.
[0107] Another object of the present invention is to provide a
method to deliver a large molecule across the blood-brain barrier
so that it is delivered to the brain in a therapeutically effective
dose and thereby treats dementia.
[0108] Another object of the present invention is to provide a
method to deliver a large molecule across the blood-brain barrier
so that it is delivered to the brain in a therapeutically effective
dose and thereby treats a brain tumor.
[0109] Another object of the present invention is to provide a
methods to deliver a molecules with a molecular weight less than
2,000 daltons across the blood-brain barrier so that it they are
delivered to the brain, the eye, or the auditory apparatus in a
therapeutically effective dose.
[0110] None of the prior art patents or articles disclose or teach
the use of perispinal administration without direct intrathecal
injection of etanercept or other large molecules, as in the present
invention, as a way of treating a brain, retina, or cranial nerve
disorder, in which said large molecule is delivered via the
vertebral venous system and provides the patient with a better
opportunity to heal, slows disease progression, improves brain or
retinal function or otherwise improves the patient's health.
[0111] Accordingly, it is an object of the present invention to
provide large molecules administered into the perispinal area,
outside of the intrathecal space, via the vertebral venous system,
as a new method of biologic treatment of neurological conditions of
the brain, retina, eye or auditory apparatus such that the use of
these large molecules will result in improved health.
[0112] Another object of the present invention is to provide large
molecules delivered via the vertebral venous system for providing
suppression and inhibition of the action of specific cytokines in a
human to treat disorders of the brain, retina, cranial nerves,
spine, spinal cord, spinal nerve roots, dorsal root ganglia or
hearing.
[0113] Another object of the present invention is to provide a
large molecule delivered via the vertebral venous system so that it
is delivered to the brain, retina, cranial nerves, or auditory
apparatus in a therapeutically effective dose and thereby improves
disorders of the brain, retina, cranial nerves, or hearing.
[0114] Another object of the present invention is to provide large
molecules that produce biologic effects in patients with vision
loss by inhibiting the inflammatory cascade in the human body for
the immediate, short term (acute conditions) and long term (chronic
conditions), such that these biologic effects will produce clinical
improvement in the patient and will give the patient a better
opportunity to heal, improve vision, slow vision loss, prevent
neurological damage, or otherwise improve the patient's health.
[0115] Another object of the present invention to provide a cancer
chemotherapeutic agent delivered via the vertebral venous system
for the treatment of a malignant disease of the brain in a human
such that the use of this cancer chemotherapeutic agent results in
decreased or delayed growth of the malignancy.
[0116] Another object of the present invention to provide
bevacizumab delivered via the vertebral venous system for the
treatment of a malignant disease of the brain in a human such that
the use of bevacizumab results in decreased or delayed growth of
the malignancy.
[0117] Another object of the present invention to provide
pegaptanib or ranibizumab delivered via the vertebral venous system
for the treatment of a malignant disease of the brain in a human
such that the use of bevacizumab results in decreased or delayed
growth of the malignancy.
[0118] Another object of the present invention to provide
pegaptanib or ranibizumab delivered via the vertebral venous system
for the treatment of ocular neovascularization in a human such that
the use of pegaptanib or ranibizumab results in improved
vision.
[0119] Another object of the present invention to provide
pegaptanib or ranibizumab delivered via perispinal administration
for the treatment of a malignant disease of the brain in a human
such that perispinal administration results in effective delivery
of pegaptanib or ranibizumab via the vertebral venous system
thereby resulting in decreased or delayed growth of the
malignancy.
[0120] Another object of the present invention to provide
pegaptanib or ranibizumab delivered via perispinal administration
for the treatment of ocular neovascularization in a human such that
perispinal administration results in effective delivery of
pegaptanib or ranibizumab via the vertebral venous system thereby
resulting in improved vision.
[0121] Another object of the present invention to provide
bevacizumab delivered via perispinal administration for the
treatment of a malignant disease of the brain in a human such that
perispinal administration results in effective delivery of
bevacizumab via the vertebral venous system thereby resulting in
decreased or delayed growth of the malignancy.
[0122] Another object of the present invention to provide a TNF
antagonist delivered via the vertebral venous system for the
treatment of sensorineural hearing loss in a human such that the
use of this antagonist results in improved hearing.
[0123] Another object of the present invention to provide a TNF
antagonist for the treatment of sensorineural hearing loss in a
human such that the use of this antagonist results in improved
hearing without the use of a hearing aid, in a manner that is both
safe and effective.
[0124] Another object of the present invention to provide a TNF
antagonist delivered via the vertebral venous system for the
treatment of vision loss in a human such that the use of this
antagonist results in improved vision without the need for
surgery.
[0125] Another object of the present invention is to provide novel
and improved routes of administration for the selected TNF
antagonist so that it enters the vertebral venous system in a
therapeutically effective amount for the treatment of macular
degeneration in a human such that the use of this antagonist with
this method results in improved vision or in delay of disease
progression in a manner that is both safe, effective, and
economical.
[0126] Another object of the present invention is to provide novel
and improved routes of administration for the selected biologic so
that it enters the vertebral venous system in a therapeutically
effective amount for the treatment of a clinical disorder of the
brain in a human such that the use of this biologic with this
method results in improved health in a manner that is both safe,
effective, and economical.
5. SUMMARY OF THE INVENTION
[0127] The present invention provides specific methods for
delivering golimumab to a mammal utilizing perispinal
administration without direct intrathecal injection. For the
purposes of this patent "perispinal" is to be considered as
referring to "perispinal extrathecal"; therefore direct intrathecal
administration is excluded from the methods discussed.
[0128] The term "treatment" as used herein in the context of
treating a condition, refers generally to the treatment and
therapy, whether a human or an animal, in which some desired
therapeutic effect is achieved, for example the inhibition of the
progression of the condition or illness, and includes the reduction
in the rate of progress, a halt in the progression of an illness,
amelioration of the adverse condition, and cure of the condition.
Treatment as a prophylactic measure, as well as combination
treatments and therapies are also included.
[0129] As used herein, "therapeutically effective" refers to the
material or amount of material which is effective to prevent,
alleviate, or ameliorate one or more symptoms or signs of a disease
or medical condition, produce clinical improvement, delay clinical
deterioration, and/or prolong survival of the subject being
treated.
[0130] As used herein, "subject" refers to animals, including
mammals, such as human beings, domesticated animals, and animals of
commercial value.
[0131] As used herein, the term "biologic" is defined as a drug
which is derived or prepared from the DNA of a living organism,
which has a relatively large molecular weight and a high structural
complexity as compared with biologically active substances which
are produced by chemical synthesis. The living sources from which
biologics may be obtained include humans, other animals, and
microorganisms. The drug may be produced by recombinant means, or
may be extracted and purified directly from the living source.
[0132] As used herein, "perispinal administration without direct
intrathecal injection" refers to administration adjacent to the
spine, but outside of the intrathecal space (extrathecal), wherein
the injection needle or catheter does not penetrate the dural
barrier. Administration therefore is not directly into the
cerebrospinal fluid.
[0133] Non-brain capillaries are made up of endothelial cells which
are separated by small gaps that allow chemicals in solution to
pass into the blood stream, where they can be transported thoughout
the body. In non-brain capillaries, compounds having molecular
weights greater than 25,000 Daltons can undergo transport. In
contrast, endothelial cells in brain capillaries are more tightly
packed, due to the existence of zonula occludentes (tight
junctions) between them, thereby blocking the passage of most
molecules. The blood-brain barrier blocks most molecules except
those that cross cell membranes by means of lipid solubility (such
as, for example, oxygen, carbon dioxide, and ethanol) and those
which are allowed in by specific transport systems (such as, for
example, sugars, amino acids, purines, nucleosides and organic
acids). Generally, it is accepted that substances having a
molecular weight greater than 500 daltons cannot cross the
blood-brain barrier, whereas substances having a molecular weight
less than 500 daltons can cross the blood-brain barrier.
[0134] Because they do not effectively cross the blood-brain
barrier, biologics having a molecular weight greater than 500 are
not effective when administered systemically. For example,
etanercept has a molecular weight of 150,000 Daltons, and is not
effective for treating conditions of the brain, eye, spinal chord,
and cranial nerves. Thus, utilization of the VVS is particularly
useful for the administration of high molecular weight biologics
such as bevacizumab or etanercept, for delivery to the brain,
retina, eye, cranial nerves, spine and spinal cord, thereby
enabling the treatment of a wide range of previously intractable
disorders of the brain, the retina, and the nervous system,
including those which are inflammatory, malignant, infectious,
autoimmune, vascular, and degenerative.
[0135] In addition the methods of the present invention may be used
to deliver molecules with a MW less than 2,000 daltons to the brain
and other structures of the head more efficiently than if delivered
systemically, and these methods utilizing these smaller molecules
are also to be considered a part of this invention.
[0136] Perispinal administration involves anatomically localized
delivery performed so as to place golimumab directly in the
vicinity of the spine, and thereby facilitate delivery of golimumab
to the brain, the eye, the retina, the auditory apparatus, the
cranial nerves, the spinal nerve roots, the dorsal root ganglia,
the spinal cord or the head. Perispinal administration includes,
but is not limited to, the following types of administration:
parenteral; subcutaneous; intramuscular; and interspinous; and
specifically includes the use of interspinous injection carried
through the skin in the midline of the neck or back, directly
overlying the spine, so that the large molecule is delivered into
the interspinous space. Perispinal administration leads to enhanced
delivery of golimumab to the brain, the eye, the retina, the
auditory apparatus, the spine and contiguous structures, and the
cranial nerves or the head in a therapeutically effective amount,
via the vertebral venous system. Delivery of a large molecule to
the brain utilizing the methods of the present invention includes
the use of the vertebral venous system to deliver the large
molecule to the brain via retrograde venous flow. Physical
positioning may also be used to enhance delivery via this
route.
[0137] All of the large molecules available for therapeutic use are
approved for systemic administration, either by subcutaneous (SC)
or intravenous (IV) administration. None have been approved for
perispinal or interspinous administration.
[0138] This patent application describes novel methods of
administration of large molecules, utilizing perispinal
administration, which results in improved efficiency (decreased
dose for equivalent therapeutic effect) and/or increased
effectiveness (increased therapeutic effect for equivalent
therapeutic dose) compared with systemic administration.
[0139] This invention is distinguished from the prior art in a
variety of ways, including the use and description of novel and
useful new uses, methods of use, and concepts involving large
molecules, including: [0140] 1. Novel uses of perispinal
administration to enhance delivery of golimumab and other large
molecules to the brain, the eye, the retina, the auditory
apparatus, the cranial nerves or the head; and [0141] 2. Novel
methods of use of large molecules; and [0142] 3. Novel concepts,
including: [0143] a. Perispinal (extrathecal) administration
distinguished from systemic forms of administration and intrathecal
administration; [0144] b. The use of the vertebral venous system to
deliver golimumab and other large molecules to the brain, the eye,
the retina, the auditory apparatus, the cranial nerves, the spinal
nerve roots, the dorsal root ganglia, the spinal cord or the head;
[0145] c. The use of physical maneuvers to facilitate delivery of
golimumab to the brain, the eye, the retina, the auditory
apparatus, the cranial nerves or the head; [0146] d. The use of
physical positioning to influence the direction of venous flow
within the vertebral venous system and thereby deliver therapeutic
molecules to the brain, the eye, the retina, the auditory
apparatus, the cranial nerves or the head; [0147] e. The use of
retrograde venous perfusion to deliver therapeutic molecules to the
brain, the eye, the retina, the auditory apparatus, the cranial
nerves or the head; [0148] f. The use of retrograde venous
perfusion via the vertebral venous system to facilitate delivery of
therapeutic molecules to the brain, the eye, the retina, the
auditory apparatus, the cranial nerves or the head; [0149] g. The
use of the vertebral venous system as a "back door" to facilitate
delivery of therapeutic molecules to the brain, the eye, the
retina, the auditory apparatus, the cranial nerves or the head;
[0150] h. The use of perispinal administration to introduce a large
molecule into the vertebral venous system; [0151] i. The use of
perispinal administration to efficiently deliver large molecules to
the brain, the eye, the retina, the auditory apparatus, the cranial
nerves, the spinal nerve roots, the dorsal root ganglia, the spinal
cord or the head.
[0152] The same methods described for golimumab of this invention
also apply to other large molecules, such as etanercept,
certolizumab pegol, IL-1 Trap, Kineret.RTM., bevacizumab,
pegaptanib, ranibizumab, rituximab, Zevalin.RTM., Mylotarg.RTM.,
Campath.RTM., HumaSpect.RTM., abatacept, cetuximab, panitumumab,
pegfilgrastim, filgrastim, erythropoietin, Aranesp.RTM.,
trastuzumab, Pegasys.RTM., Intron A.RTM., PEG-Intron.RTM.,
Infergen.RTM., Avonex.RTM., Rebif.RTM., Betaseron.RTM.,
Actimmune.RTM., Ontak.RTM., Simulect.RTM., Zenapax.RTM.,
Genkaxin.RTM., recombinant human growth hormone, reteplase,
alteplase, tPA (tissue plasminogen activator), urokinase
plasminogen activator, streptokinase, urokinase, or immune
globulin), and smaller molecules, such as Tarceva.RTM., all of
which maybe given by perispinal administration, and whose use, by
perispinal administration without direct intrathecal injection,
constitute part of this invention.
6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0153] The use of perispinal administration of cytokine antagonists
to treat neurological disorders is discussed in US patent
application 20030049256 of this inventor. The use of perispinal
administration without direct intrathecal injection and the
vertebral venous system to deliver large molecules to the brain,
the eye, and the auditory apparatus are discussed in the following
provisional patent applications: [0154] 60/585,735 filed Jul. 6,
2004; [0155] 60/659,414 filed Mar. 9, 2005; [0156] 60/662,744 filed
Mar. 17, 2005; [0157] and 60/669,022, filed Apr. 7, 2005,
[0158] This is a continuation-in-part of U.S. patent application
Ser. No. 11/016,047, filed Dec. 18, 2004, entitled "Methods of use
of etanercept to improve human cognitive function", which is a
continuation-in-part of U.S. Patent Application 20030049256, also
known as U.S. patent application Ser. No. 10/269,745, entitled
"Cytokine antagonists for neurological and neuropsychiatric
disorders", filed Oct. 9, 2002, now U.S. Pat. No. 6,982,089, which
is a continuation-in-part of Ser. No. 10/236,097, filed on Sep. 6,
2002, now abandoned, which is a continuation-in-part of application
Ser. No. 09/841,844, filed on Apr. 25, 2001, now U.S. Pat. No.
6,537,549, which is a continuation-in-part of application Ser. No.
09/826,976, filed on Apr. 5, 2001, now U.S. Pat. No. 6,419,944,
which is a continuation-in-part of application Ser. No. 09/563,651,
filed on May 2, 2000, which is a continuation-in-part of
application Ser. No. 09/476,643, filed on Dec. 31, 1999, now U.S.
Pat. No. 6,177,077, which is a continuation-in-part of application
Ser. No. 09/275,070, filed on Mar. 23, 1999, now U.S. Pat. No.
6,015,557, which is a continuation-in-part of application Ser. No.
09/256,388, filed on Feb. 24, 1999, now abandoned. This application
is also related to provisional U.S. patent application 60/662,744
entitled "Methods of Use of the Vertebral Venous System to Deliver
Biologics to the CNS" filed Mar. 16, 2005. The use of perispinal
administration of cytokine antagonists to treat neurological
disorders is discussed in US patent application 20030049256 of this
inventor. The use of perispinal administration without direct
intrathecal injection and the vertebral venous system to deliver
large molecules to the brain, the eye, and the auditory apparatus
are discussed in provisional patent applications 60/585,735 filed
Jul. 6, 2004; 60/659,414 filed Mar. 9, 2005; 60/662,744 filed Mar.
17, 2005; and 60/669,022, filed Apr. 7, 2005. In addition this
provisional patent application is related to Atty. Docket No.
"Tobinick 3.0-027 (Prov)" U.S. provisional patent application
entitled "Methods to facilitate transmission of golimumab and other
therapeutic molecules across the blood-brain-barrier" filed with
the USPTO on Nov. 18, 2005.
[0159] All of the above patents and patent applications enumerated
in the above three paragraphs are incorporated by reference in
their entirety herein.
[0160] Perispinal administration of a molecule when compared to
systemic administration, carries with it one or more of the
following advantages for the present invention: [0161] 1) greatly
improved efficacy due to improved delivery of the therapeutic
molecule to the brain, the eye, the retina, the auditory apparatus,
the cranial nerves, the spinal nerve roots, the dorsal root
ganglia, the spinal cord or the head via the vertebral venous
system (VVS). [0162] 2) greater efficacy due to the achievement of
higher local concentration in the interspinous space, leading to
improved delivery to the VVS and the brain, the eye, the retina,
the auditory apparatus, the cranial nerves, the spinal nerve roots,
the dorsal root ganglia, the spinal cord or the head. [0163] 3)
greater efficacy due to the ability of the administered therapeutic
molecule to reach the brain, the eye, the retina, the auditory
apparatus, the cranial nerves, the spinal nerve roots, the dorsal
root ganglia, the spinal cord or the head without degradation
caused by hepatic or systemic circulation; [0164] 4) more rapid
onset of action; [0165] 5) longer duration of action; and [0166] 6)
Potentially fewer side effects, due to lower required dosage.
[0167] These advantages apply to both large molecules, such as
monoclonal antibodies, which typically have a MW of more than
100,000 daltons, and to smaller molecules, many of which, even
though they have a MW less than 2,000 daltons, have difficulty
traversing the BBB. Even smaller molecules, those with a MW less
than 500 daltons, which often can cross the BBB, will achieve a
greater therapeutic concentration in brain or eye tissue if
administered by perispinal delivery without direct intrathecal
injection, especially if immediately following injection the
postural adjustments are made to direct the head downward with the
body in a Trendelenburg position, thereby facilitating retrograde
venous perfusion via the intracranial anastomoses of the vertebral
venous system. The blood-eye barrier, for the purposes of this
patent, will be traversed by the methods of the present invention
in a manner equivalent to the manner in which these molecules cross
the blood-brain barrier. The blood-nerve barrier protecting the
spinal nerve roots and the spinal cord, consisting in large part of
the barrier formed by the dura mater, will also be traversed in a
manner utilizing the methods of the present invention i.e. by
carriage in the vertebral venous system, etc.
[0168] The inventor has extensive clinical experience utilizing
perispinal injection of etanercept for the treatment of
disc-related pain and radiculopathy, including low back pain, neck
pain, lumbar radiculopathy (sciatica), cervical radiculopathy, pain
associated with annular tear of the intervertebral disc, and pain
associated with degenerative disc disease (see Tobinick reference
63) (Tobinick, E. and S. Davoodifar, Efficacy of etanercept
delivered by perispinal administration for chronic back and/or neck
disc-related pain: a study of clinical observations in 143
patients. Curr Med Res Opin, 2004. 20(7): p. 1075-85). In this
article the inventor reported the results of perispinal etanercept
treatment for 143 patients, including those with disc bulge,
protrusion, extrusion or herniation; lumbar and cervical
radiculopathy; degenerative disc disease; central spinal stenosis;
spondylolisthesis; back pain, neck pain, or sciatica; and annular
tear of the intervertebral disc. The 143 patients had a mean
duration of pain of 9.8 years. After a mean of 2.3 doses of
perispinal etanercept the mean VAS intensity of pain, sensory
disturbance, and weakness was significantly reduced at 20 min., 1
day, 1 week, 2 weeks, and 1 month. In a previous publication
(Tobinick, E. L. and S. Britschgi-Davoodifar, Perispinal TNF-alpha
inhibition for discogenic pain. Swiss Med Wkly, 2003. 133(11-12):
p. 170-7) the inventor documented clinical improvement following
perispinal etanercept in a cohort of 20 patients with the following
diagnoses: acute lumbar radiculopathy; chronic cervical and lumbar
discogenic pain; subacute lumbar radiculopathy; chronic discogenic
pain and failed back surgery syndrome; chronic low back pain and
sciatica; chronic, treatment-resistant discogenic pain. Rapid,
substantial, and sustained clinical pain reduction and improvement
in functional disability was documented in this group of patients
for a mean of 230 days. At the time that these articles were
published the inventor was not aware of the fact that the vertebral
venous system drains the perispinal area, including both the deeper
interspinous space superficial to the ligamentum flavum and the
subcutaneous perispinal space which overlies the spinous processes
and the deeper interspinous space. It is a method of the present
invention to introduce large molecules into this area (the
perispinal area) to enable them to drain into the vertebral venous
system and thereby cross the blood-nerve barrier and produce
therapeutic benefit for treating the spinal conditions enumerated
in this paragraph. This may be accomplished by perispinal injection
of these molecules, which leads to entry of the large molecules
into the vertebral venous system, and then delivery of these
molecules, by retrograde venous flow due to lack of venous valves
in the VVS, to the spinal nerve roots, the dorsal root ganglia, and
the spinal cord. In the case of etanercept and golimumab, for
example, this results in neutralization of excess TNF and clinical
improvement in patients suffering from a variety of spinal
ailments, including specifically those enumerated in this
paragraph. The dosage needed to accomplish this is outlined in the
above articles (references 63 and 64) and elsewhere in this patent
application with respect to etanercept. For golimumab, the dosage
used will vary between 10 and 100 mg, including a dosage of 25 mg
or 50 mg given as a perispinal extrathecal injection.
[0169] The inventor has successful clinical experience with
perispinal administration of etanercept, a large molecule (MW
149,000 daltons) for the treatment of Alzheimer's Disease (AD) (see
experimental results infra) which illustrates the clinical efficacy
of this method of delivery of large molecules for the treatment of
brain disorders, and, specifically, the ability of this delivery
method to enable etanercept to cross the BBB and effectively treat
AD. It should be noted that a previous clinical trial utilizing
etanercept (reference 61) delivered systemically (by subcutaneous
administration remote from the spine) failed to show efficacy,
thereby providing prima facie evidence of the superiority of
perispinal administration to deliver etanercept to the brain, when
a comparison of the failed trial results to the successful
experimental results obtained utilizing perispinal administration
of etanercept, detailed infra, is made. The methods described
herein involve the use of perispinal administration to effectively
deliver large molecules to the brain, the eye, the retina, the
auditory apparatus, the cranial nerves or the head, for therapeutic
use in humans and other mammals.
[0170] The VVS consists of an interconnected and richly anastomosed
system of veins which run along the entire length of the vertebral
canal. The vertebral venous plexus, for descriptive purposes, has
been separated into three intercommunicating divisions: the
internal vertebral venous plexuses (anterior and posterior) lying
within the spinal canal, but external to the dura; the external
vertebral venous plexuses (anterior and posterior) which surround
the vertebral column; and the basivertebral veins which run
horizontally within the vertebrae (see FIG. 1, drawn by Frank
Netter, MD, which follows the text portion of this patent
application and is included as an integral part of the
application). Both the internal and external vertebral venous
plexus course longitudinally along the entire length of the spine,
from the sacrum to the cranial vault. Utilizing corrosion casting
and injections of Araldite, Clemens demonstrated that the internal
and external vertebral venous plexuses freely intercommunicate, and
this was also demonstrated by Vogelsang with the use of
intraosseous spinal venography. Groen and his colleagues with an
improved Araldite injection technique which utilized thrombolytics,
confirmed the fact that all three divisions of the vertebral venous
system (internal and external plexuses, and the basivertebral
veins) freely intercommunicated, and that all divisions of this
system lacked valves. The internal vertebral venous plexus
communicates with the intraspinal and radicular veins and freely
communicates with the external vertebral venous plexus via the
intervertebral veins (see references 44-50). In addition, the VVS
communicates with the azygous veins, and has other connections to
the caval venous system, but not efficiently. Therefore a
conventional intravenous injection in the antecubital fossa, for
example, or into one of the large veins of the forearm, which
delivers a solution containing a given therapeutic molecule into
the caval venous system, does not efficiently deliver the same
therapeutic molecule to the VVS. Likewise, delivery of a solution
containing a given therapeutic molecule by perispinal
administration will not result in efficient delivery of the given
therapeutic molecule into the caval venous system, but will result
in efficient delivery into the VVS. The caval venous system and the
VVS are separate and largely independent (see reference 59),
although they are interconnected, although not in an efficient
manner. To phrase the same thoughts in a different way, it would be
accurate to say that perispinal administration of a large molecule
will result in efficient delivery of the large molecule to the VVS,
with only a small amount of delivery of the large molecule into the
caval venous system. Delivery of the same large molecule by
intravenous infusion into an arm vein, for example, will deliver
the large molecule to the caval venous system, expose the large
molecule to dilution throughout the body, and fail to deliver the
large molecule to the brain, the eye, the retina, the auditory
apparatus, the cranial nerves or the head.
[0171] A specific anatomic route, by which a large molecule
delivered by perispinal administration reaches the brain, has been
defined by the inventor (see FIG. 2). This route is as follows. A
large molecule is delivered to the interspinous space in proximity
to the ligamentum flavum by percutaneous injection through the skin
by midline interspinous needle injection. Large molecules delivered
to the interspinous space in this way (being the anatomic region in
the midline of the back, in-between two adjacent spinous processes)
are delivered into the VVS because the VVS serves to provide venous
drainage to the interspinous space and subcutaneous space which is
posterior to the spine (see Batson references 48 and 49 for a
discussion of the VVS, which, however, does not discuss the
therapeutic potential of the VVS). Solutions injected into this
area, therefore, will be preferentially absorbed into the VVS
rather than into the caval venous system. In addition, a more
direct route to the epidural space is also possible for solutions
injected into the interspinous space, by travel through midline
defects in the ligamentum flavum. Midline defects in the ligamentum
flavum are common, particularly in the cervical region. When
present the midline ligamentum flavum defect provides a direct
route of access for large molecules to the epidural space. Within
the epidural space lies a richly interconnected venous plexus
(which is part of the VVS), which is valveless and which is capable
of transporting large molecules rapidly in the cephalad or caudad
directions (see Batson references 48 and 49). Flow within the VVS
is bidirectional. Therefore large molecules injected into the
interspinous space drain directly into the VVS and thereby gain
direct access to the brain, if the patient is positioned properly
immediately following injection so that gravity is used to direct
flow via the VVS toward the brain. This is possible because the
flow within the VVS can be bidirectional; therefore these veins
serve not only to drain blood from the brain, but also to deliver
venous blood to the brain, in retrograde fashion, via the venous
connections of the VVS with the intracranial venous system,
including the dural sinuses. This retrograde flow is made possible
by the lack of venous valves in the VVS. Retrograde venous delivery
of large molecules to the brain is a method of the present
invention and a discovery of the inventor. The author has detailed
much of his current thinking regarding the vertebral venous system
and its connection with the cerebral venous system in a recently
published article entitled "The Cerebrospinal Venous System:
Anatomy, Physiology, and Clinical Implications" published in
Medscape General Medicine in February 2006 (MedGenMed. 2006 Feb.
22; 8(1):53.) This article is incorporated in its entirety in this
patent application by reference.
[0172] The VVS can be used to deliver large biologic therapeutic
agents (i.e., biologics having a molecular weight greater than 600
Daltons, preferably greater than 2000 Daltons) utilizing retrograde
venous flow from the VVS into the cranial venous sinuses and the
intracranial venous system for delivery to the cerebral cortex,
eye, retina, spine, cerebellum, brainstem, eighth cranial nerve,
cochlea, inner ear, cerebrospinal fluid, spine, spinal cord, dorsal
root ganglion, spinal nerve roots, reproductive organs and spinal
nerve roots of a subject. Exemplary pharmaceutically acceptable
therapeutic agents may include pharmacologic agents, cytokine
antagonists and growth factors which can affect neuronal function
or the immune response impacting neuronal function, including, but
not limited to, for example, golimumab, CDP 870, and
etanercept.
[0173] Retrograde venous delivery of large molecules to the brain
is facilitated by body positioning after interspinous injection.
For example, if following cervical interspinous injection the
patient is placed in the head down trendelenburg position then the
inventor has discovered that this will lead to effective delivery
of the large molecule to the brain, via retrograde flow in the VVS
into the cranial venous system.
BRIEF DESCRIPTION OF THE FIGURES ACCOMPANYING THE TEXT PORTION OF
THIS APPLICATION
[0174] FIG. 1 is a scan of a photograph, taken at the National
Library of Medicine, of plate 5 drawn by Breschet and published in
1828 (reference 56), depicting the cranial and vertebral venous
systems, their anastomoses, and their anatomic characteristics,
especially in relationship to other anatomic features of the brain
and spine.
[0175] FIG. 2 is a diagram depicting perispinal administration, in
accordance with the present invention.
[0176] FIG. 3 are drawings by Frank Netter, MD depicting three
different anatomic views of the vertebral venous system (VVS) and
its anatomic relationship to the interspinous space and other
anatomic elements of the spine.
[0177] FIG. 1 depicts the anastomoses between the cranial and
vertebral venous systems. Perispinal administration for delivery to
the brain and other structures of the head is preferably performed
by a percutaneous injection into an interspinous space in the
posterior cervical area (12 in FIG. 2). As shown in more detail in
FIG. 2, hollow needle (26) containing etanercept (or other
therapeutic molecule of this invention) in solution (30) is
injected through the skin 18 into the interspinous space 24. If the
needle were carried further it could penetrate the ligamentum
flavum (22), delivering the therapeutic molecule into the epidural
space (28) surrounding the spinal cord (36), although in most
iterations of this invention the ligamentum flavum is not
penetrated by the needle, and the therapeutic molecule is deposited
into the interspinous space more superficially, without penetration
of the ligamentum flavum. The therapeutic molecule in the
interspinous space drains into the vertebral venous system, and is
then carried to the brain, the eye, the auditory apparatus, and
other structures of the head. (34) is a spinal nerve root.
[0178] The interspinous space (24) is defined as the space between
two adjacent spinous processes (20). FIG. 3 shows the interspinous
space (24) having veins (38) (FIG. 3) which collect the therapeutic
molecule, in this case etanercept, which reaches the interspinous
space after percutaneous interspinous injection and which veins
drain said therapeutic molecule into the VVS, so that, utilizing
the physical maneuvers of the present invention, the therapeutic
molecule is transported via retrograde venous flow into the
intracranial veins via the anastomoses depicted in FIG. 1, and
thence to the brain, the eye, the auditory apparatus, or other
structures of the head.
[0179] The inventor is using the vertebral venous system in a
non-obvious way for the inventions disclosed herein. For a venous
system is routinely conceptualized as a system that drains blood
from a target area or organ. For example the venous system which
drains the kidneys is widely acknowledged to be a vascular system
that drains blood from the kidneys, not as a way of delivering a
therapeutic molecule to the kidneys. Likewise the venous system of
the brain is widely medically recognized as a system which
functions to drain blood from the brain. It would be
counter-intuitive to propose using the VVS to deliver a therapeutic
molecule to the brain, by conventional thinking. Likewise the use
of the vertebral venous system to achieve delivery of therapeutic
compounds to the brain is not obvious, because conventional
thinking is that this venous system functions to drain venous blood
away from these anatomic sites. Therefore the inventions of
consideration here are in this way counter-intuitive, because they
rely on the vertebral venous system to deliver therapeutic
molecules (including specifically large molecules) to the brain,
the eye, the retina, the auditory apparatus, the cranial nerves or
the head. This delivery is accomplished by retrograde venous flow
(opposite from the usual direction), which is made possible by the
lack of valves in this venous system, and by the proper use of
gravity and positioning of the patient so that venous flow in the
desired direction is accomplished. The rich connections between the
cranial venous system and the vertebral venous system were
beautifully depicted in 1828 by Breschet (reference 56), but this
anatomic route remains largely unrecognized by the medical
community till the present time.
[0180] Correct positioning of the patient so as to facilitate
retrograde flow in the desired direction is utilized as part of the
present invention to achieve improved delivery of golimumab and
other large molecules to the brain, the eye, the retina, the
auditory apparatus, the cranial nerves or the head from its
injection point. Since the target is delivery of the large molecule
to the brain, the eye, the retina, the auditory apparatus, the
cranial nerves or the head, positioning following delivery
utilizing head-down trendelenburg positioning, assists in
delivering the large molecule to the target. In most cases, for
delivery of a large molecule to the brain, the eye, the retina, the
auditory apparatus, the cranial nerves or the head, interspinous
injection is peformed overlying the posterior aspect of the
cervical spine, in the interspinous region between the C4 and C8
spinal processes, followed by placement of the patient in the
head-down trendelenburg position, usually in the prone position, if
possible, since the large molecule is delivered, as described, to
an area dorsal to the spine.
[0181] Batson's plexus may be used to introduce a variety of
therapeutic molecules to the brain, retina, cranial nerves, and
head via retrograde venous flow from Batson's plexus into the
cranial venous sinuses and the intracranial venous system. This
method bypasses the well known barrier which prevents large
molecules introduced into the systemic circulation from reaching
the brain (the BBB). The BBB prevents molecules larger than
approximately 600 daltons from entering the brain via the systemic
circulation. Virtually all biopharmaceuticals are larger than this.
For example, etanercept has a molecular weight of 149,000 daltons,
and insulin has a MW of 5,000 (compared with water which has a MW
of 18). This method is particularly useful, therefore, for the
administration of biologics, such as etanercept, erythropoietin,
GM-CSF, ranibizumab, etc., whose size when delivered systemically
prevents their efficient passage into the brain, retina, eye, and
cranial nerves, but whose potency, because of their biologic
origin, is extremely high. Effective delivery of these molecules to
the brain, the retina, the eye, and the cranial nerves using the
methods of the present invention thereby enables the treatment of a
wide range of previously intractable disorders of the brain, the
retina, and the nervous system, including those which are
inflammatory; malignant; infectious; autoimmune; vascular; and
degenerative.
[0182] The vertebral venous system is both anatomically and
physiologically distinct from the venous system which drains the
abdomen and thorax, which has been designated by others as the
intracavitary venous system, with the vertebral venous system
designated as the extracavitary venous system. Other nomenclature
for the VVS also comes to mind, such as the valveless venous
system, or the bi-directional venous system, but they are perhaps
less suitable than the VVS. The VVS and the intracavitary venous
system also share anastomoses, as has been discussed at length by
Batson. Batson has also described the retrograde flow possible with
the VVS, but has not proposed the possible use of the VVS as a
route to deliver therapeutic compounds, nor has anyone else. Again,
this retrograde route of delivery is uniquely possible utilizing
the VVS because of the lack of venous valves.
[0183] Use of the vertebral venous system as a route to deliver
golimumab to the retina, eye or optic nerve via retrograde venous
flow is a novel new delivery method for treating disorders of the
brain, retina, eye or optic nerve.
[0184] This method allows the treatment of inflammatory or
degenerative disorders of the retina and/or optic nerve, such as
macular degeneration, diabetic retinopathy, glaucoma and retinitis
pigmentosa, which involve excessive levels of TNF or which are
mediated by VEGF. Excess TNF appears to have a direct deleterious
effect on vision, and etanercept, delivered via the vertebral
venous system, appears to have the ability to ameliorate this
adverse effect. Perispinal administration of these biologics
enables the biologic to reach the internal contents of the eye,
including the choroidal vasculature and the retina, in therapeutic
amounts, via retrograde flow within the cranio-vertebral venous
system.
[0185] The methods of the present invention include the perispinal
administration of the biologics of consideration herein (listed
below), which can be accomplished in various ways, including
transcutaneous interspinous injection, or catheter delivery into
the epidural or interspinous space, which results in the biologics
being delivered into the vertebral venous system and thence into
the brain, retina, cranial nerves, and auditory apparatus in a
therapeutic amount.
[0186] As defined herein, the auditory apparatus includes the
cochlea, the auditory division of the eighth cranial nerve, and the
central auditory pathways. Sensorineural hearing loss is one
particular category of hearing loss and is caused by lesions of the
cochlea and/or the auditory division of the eighth cranial nerve.
Prior to this invention, treatment of this condition was primarily
limited to the use of hearing aids.
[0187] Midline interspinous administration of etanercept has been
demonstrated (see below) to produce improvement in hearing to
individuals with certain forms of non-conductive hearing loss. In
addition to percutaneous injection into the interspinous space,
etanercept may also be delivered to the interspinous or epidural
space by implantable catheter, with the catheter reservoir placed
remotely, such as in the abdominal area.
[0188] The inventor first described improvement in hearing in a 73
y.o. patient after perispinal administration of etanercept for the
treatment of sciatica in U.S. Pat. No. 6,423,321. The anatomic
route which enables the efficient delivery of perispinal etanercept
to the brain is identified by the inventor, and physical maneuvers
to facilitate this process are described herein. For the purposes
of this patent perispinal etanercept is distinguished from the use
of etanercept delivered by subcutaneous administration at anatomic
sites, such as the abdomen, thighs, and arms, which are remote from
the spine.
[0189] Bevacizumab (Avastin.TM., Genentech) is a recombinant
humanized monoclonal IgG1 antibody that binds to and inhibits the
biologic activity of human vascular endothelial growth factor
(VEGF) and which may be useful for the treatment of retinal
disorders which involve neovascularization. Bevacizumab has a
molecular weight of 149,000 daltons and is therefore too large to
readily cross the blood-brain barrier if administered systemically.
Administration of bevacizumab via the vertebral venous system
bypasses the blood-brain barrier and allows a therapeutic dose of
bevacizumab to reach the retina, therefore enabling the treatment
of retinal disorders which involve neovascularization, including
macular degeneration and diabetic retinopathy. For this purpose
bevacizumab may be administered via perispinal administration,
thereby providing access of this monoclonal antibody to the VVS and
therefore to the retina.
[0190] Pegaptanib and ranibizumab are two biologics which are
antagonists of human vascular endothelial growth factor (VEGF) and
which may be useful for the treatment of retinal disorders which
involve neovascularization. Pegaptanib is a VEGF-neutralizing
oligonucleotide aptamer which binds and sequesters VEGF, thereby
preventing VEGF receptor activation. Ranibizumab is a recombinant
humanized monoclonal antibody fragment with specificity for VEGF.
Both pegaptanib and ranibizumab are too large to readily cross the
blood-brain barrier or the blood-ocular barrier if administered
systemically. They have both shown some efficacy in treating ocular
neovasculariztion when administered by injection into the eye by
the intravitreal route. Administration of these agents via the
vertebral venous system bypasses the blood-brain barrier and the
blood-ocular barrier and allows a therapeutic dose to reach the
retina, therefore enabling the treatment of retinal disorders which
involve neovascularization, including macular degeneration and
diabetic retinopathy, without the necessity for intravitreal
injection. For this purpose pegaptanib and ranibizumab may be
administered via perispinal administration, thereby providing
access of biologics to the VVS and therefore to the retina, the
choroidal vessels, and the eye without requiring intravitreal
injection. Additionally perispinal injection of these two biologics
will enable effective delivery of these agents to the brain,
thereby allowing the use of these agents for brain tumors and other
clinical disorders which will respond positively to modulation of
VEGF.
[0191] Perispinal administration for delivery of neuroactive
molecules other than etanercept, including biologics, cytokines,
anti-cytokines, hormones or drugs via the vertebral venous system,
in a manner similar to that outlined herein, may be performed. The
neuroactive compounds include the individual interleukins IL-1,
IL-2, IL-4, IL-6, IL-10, or IL-13; interleukin 1 antagonists, such
as IL-1 RA (Kineret.RTM., Amgen) and IL-1 Trap; fusion proteins,
such as IL-10 fusion protein or etanercept (Enbrel.RTM., Immunex);
other TNF antagonists, including certolizumab pegol, soluble TNF
receptor type I or pegylated soluble TNF receptor type 1; human
growth hormone and related biologics (recombinant human growth
hormone, Humatrope.RTM. (somatropin) Eli Lilly & Co.,
Nutropin.RTM./Nutropin AQ.RTM. (somatropin), Geref.RTM.
(sermorelin) Serono, and Protropin.RTM. (somatrem) Genentech));
BDNF; erythropoietin (Epogen.RTM. (epoetin alpha) Amgen,
Procrit.RTM. (epoetin alpha) Johnson & Johnson); G-CSF
(Neupogen.RTM. (filgrastim), Amgen); GM-CSF; Intron.RTM. A
(interferon alfa-2b) Schering-Plough; Avonex.RTM. (interferon
beta-1a) Biogen; Alefacept (LFA-3/IgG1 human fusion protein,
Amevive.RTM. Biogen); Epidermal growth factor; anti-EGF (ABX-EGF,
Abgenix); transforming growth factor-beta 1 (TGF-beta 1); NGF;
bevacizumab (Avastin.TM., Genentech); Copaxone.RTM. (glatiramer
acetate), pegaptanib or ranibizumab as discussed above; or other
compounds with CNS, immune, or vascular therapeutic activity.
[0192] In particular this invention involves the perispinal
administration of golimumab. Golimumab is currently in clinical
development by Centocor/Schering-Plough for treatment of rheumatoid
arthritis, with potential applications for uveitis, asthma, and
Crohn's Disease. It may be described as a immunoglobulin G1,
anti-(human tumor necrosis factor .alpha.) (human monoclonal CNTO
148 .gamma.1-chain), disulfide with human monoclonal CNTO 148
.kappa.-chain), dimer, and has CAS Registry number 476181-74-5. It
is a fully human anti-TNF monoclonal antibody.
[0193] This invention involves the use of the above molecules
delivered via the vertebral venous system either alone, as
monotherapy, or combined with the use of other therapeutics
delivered orally or otherwise for treatment of the conditions of
consideration herein. For example, the inventor has demonstrated
improvement in cognitive function in individuals with MCI or AD
treated with either perispinal etanercept alone, or perispinal
etanercept in combination with memantine and/or a cholinesterase
inhibitor (chosen from the group of donepezil, rivastigmine or
galantamine).
[0194] A biologic delivered via the vertebral venous system to the
retina and the eye after perispinal administration is specifically
included as an invention of the current patent.
[0195] The methods of the present invention are also distinguished
from direct intrathecal administration of large molecules.
[0196] The large molecules of the current invention include, but
are not limited to, the following: [0197] a. Colony-stimulating
factors (including G-CSF, such as filgrastim, pegfilgrastim, and
lenograstim; GM-CSF, including, but not limited to sargramostim and
molgramostim; Erythroid growth factors, including, but not limited
to: recombinant erythropoietin (EPO): epoetin alpha, darbepoetin
alpha; and others. [0198] b. TNF antagonists with a molecular
weight greater than or equal to 2,000 daltons, including, but not
limited to: golimumab, etanercept, infliximab, certolizumab (CDP
870, Cimzia.RTM.), CDP 571, onercept, pegylated soluble TNF
receptor type I, soluble TNF receptor type I. [0199] c.
Interferons, interferon antagonists, and interferon fusion
proteins, including, but not limited to: IL-1 Trap; Interferon
alfa-2a, rDNA [Interferon alfa-2a-Roferon A; Interferon, alpha-2a,
recombinant]; Interferon alfa-2a, rDNA, PEG-[Peginterferon
alfa-2a-Pegasys; interferon alpha-2a, recombinant, pegylated];
Interferon alfa-2b, rDNA [Interferon alfa-2-Intron A; Interferon,
alpha-2b, recombinant]; Interferon alfa-2b, rDNA,
PEG-[Peginterferon alfa-2b-PEG-Intron Powder; interferon alpha-2b,
recombinant, pegylated]; Interferon alfa, rDNA/BioPartners
[Interferon alpha, recombinant]; Interferon alfacon-1, rDNA
[Interferon alfacon-1-Infergen; consensus interferon, recombinant];
Interferon beta-1a, rDNA/Biogen [Interferon beta-1a-Avonex
[recombinant]]; Interferon beta-1a, rDNA/Serono [Interferon
beta-1a-Rebif [recombinant]]; Interferon betaser, rDNA/Berlex
[Interferon beta-1b--Betaseron] (Betaseron has a MW of 18500
daltons); 2-166-Interferon beta1 (human fibroblast reduced),
17-L-serine-; interferon betaser, recombinant]; Interferon gamma,
rDNA [Interferon gamma-1b--Actimmune; [recombinant]];
Interleukin-1ra, rDNA [Anakinra--Kineret; interleukin-1 receptor
antagonist; IL-1i]; Interleukin-2, rDNA [Aldesleukin--Proleukin;
des-alanyl-1, serine-125 interleukin-2, recombinant; IL-2];
Interleukin-2/diphtheria toxin, rDNA [Denileukin diftitox--ONTAK;
Interleukin-2 Fusion Protein; DAB389IL-2; interleukin-2/diphtheria
toxin fusion protein, recombinant]; MRA (Roche, Chugai), a
humanized anti-IL-6 receptor monoclonal antibody; Interleukin-2
receptor Mab, rDNA/Novartis [Basiliximab--Simulect; Interleukin-2
alpha receptor monoclonal antibody, recombinant]; Interleukin-2
receptor Mab, rDNA/Roche [Daclizumab--Zenapax; Interleukin-2 alpha
receptor monoclonal antibody, recombinant]; Interleukin-11, rDNA
[Oprelvekin--Neumega; des-Pro Interleukin-11, recombinant; des-Pro
IL-11]; IL-6; IL-12; anti-IL-6; and anti-IL-12. As a general rule,
interferons have molecular weights ranging from 15,000 to 21,000
daltons. [0200] d. Antibiotics with a molecular weight of 2,000
daltons or greater; [0201] e. Cancer chemotherapeutic agents, with
a molecular weight greater than or equal to 2,000, including those
from the following classes: [0202] i. Monoclonal antibodies (mAb):
including, but not limited to: [0203] 1. Rituximab, a chimeric
murine mAb against the CD20 antigen on B-lymphoma cells. [0204] 2.
Epratuzumab, a humanized mouse anti-CD22 mAb. [0205] 3.
Alemtuzumab, a humanized mAb against CD 52 on B and T lymphoma
cells. [0206] 4. Natalizumab, a humanized mAb against the alpha4
subunit of the alpha4Beta1 and Beta 7 integrins. [0207] ii.
Conjugates: Monoclonal antibody-drug, -toxin, or -radionuclide
conjugates. These antibodies recognize specific antigenic
determinants on malignant cells and their conjugates provide
selective toxicity to those cells. A monoclonal antibody conjugate,
for the purpose of this invention, is defined as a monoclonal
antibody which is conjugated to either a drug, a toxin (such as
diptheria toxin) or a radionuclide. These conjugates are
particularly suited to perispinal administration, since they are
extremely effective, even at low concentration, due to their
biologic origin, and can be effectively delivered to the brain or
to a brain tumor or lymphoma via the VVS by retrograde venous
delivery into the brain. Therefore this class of therapeutic is
effective for treating malignant tumors of the brain, either
primary, such as glioblastoma multiforme, or metastatic, and for
treating CNS lymphomas. These agents include yttrium-90
ibritummomab tiuxetan (Zevalin.RTM.) and iodine-131 tositumomab
(Bexxar.RTM.) which are both murine mAbs against CD20 antigen that
are conjugated to a radioactive source and thus selectively deliver
radiation to tumors expressing the CD20 antigen (primarily
expressed on B-lymphomas).
[0208] The above methods detailed for large molecules may be used
identically for molecules with a MW of less than 2,000 daltons. The
rationale for doing this is that many of these molecules, despite
their smaller size, still have difficulty traversing the
blood-brain barrier if administered systemically; or perispinal
delivery without direct intrathecal injection results in more
efficient delivery of these smaller molecules to the brain, the
eye, or the auditory apparatus than does systemic or oral delivery.
Perispinal administration and delivery to the brain, the eye, or
other structures of the head thereby has the advantage of more
efficient delivery across the BBB. For example the taxanes, which
include paclitaxel (Taxol.RTM.) and docetaxel (Taxotere.RTM.) have
very low BBB penetration when given systemically, despite their
respective MW of 854 and 862. Doxorubicin has poor BBB penetration
when given systemically despite its MW of 544. Methotrexate and
Amphotericin B have poor BBB penetration when given systemically,
despite a MW of 454 and 924, respectively, and are often
administered intrathecally for CNS use. The perispinal extrathecal
methods of the present invention are distinguished from direct
intrathecal injection.
[0209] With respect to the small molecules of the present
invention, they may be categorized as follows: [0210] 1. Cancer
chemotherapeutic agents, with a molecular weight less than 2,000,
including, but not limited to those from the following classes:
(Clinical use: treatment of tumors of the central nervous system or
the orbit utilizing perispinal administration without direct
intrathecal injection of the following): [0211] i. Alkaloids:
vincristine, vinblastine, vindesine, paclitaxel (Taxol.RTM.),
docetaxel, etoposide, teniposide. [0212] ii. Alkylating agents:
nitrogen mustards, nitrosureas, cyclophosphamide, thiotepa,
mitomycin C, dacarbazine. [0213] iii. Antibiotics: Actinomycin D,
daunorubicin, doxorubicin, idarubicin, mitoxanthrone, bleomycin,
mithramycin. [0214] iv. Antimetabolites: methotrexate,
6-mercaptopurine, pentostatin, 5-fluorouracil, cytosine
arabinoside, fludarabine, 2-CDA. [0215] v. Platinum compounds:
Cisplatin. [0216] vi. Others: tamoxifen (MW 563), flutamide (MW
276), anastrozole (MW 293), gefitinib (Iressa.RTM.) and erlotinib
(Tarceva.RTM.) (MW 429). [0217] 2. Antibiotics: (Clinical use:
treatment of bacterial infections of the central nervous system or
the eye utilizing perispinal administration without direct
intrathecal injection of the following): including, but not limited
to cephalosporins, tetracyclines, macrolides, fluroquinolones.
[0218] 3. Antivirals: (Clinical use: treatment of viral infections
of the central nervous system, particularly meningitis or
encephalitis or the eye utilizing perispinal administration without
direct intrathecal injection of the following): including, but not
limited to oseltamivir, zanamivir, amantadine, anti-HIV drugs,
anti-herpes drugs (including acyclovir, famciclovir, valacyclovir),
anti-CMV drugs (cidofovir, foscarnet, ganciclovir) and ribavirin.
[0219] 4. Antifungal agents: (Clinical use: treatment of fungal
infections of the central nervous system or the eye utilizing
perispinal administration without direct intrathecal injection of
the following): Amphotericin B and its congeners. [0220] 5.
Anti-parkinson drugs: (Clinical use: treatment of Parkinson's
Disease utilizing perispinal administration without direct
intrathecal injection of the following): including, but not limited
to levodopa, carbidopa, bromocriptine, selegiline, and dopamine.
[0221] 6. Anti-psychotic agents: (Clinical use: treatment of
psychoses, including schizophrenia, utilizing perispinal
administration without direct intrathecal injection of the
following): haloperidol, Prolixin.RTM., Moban.RTM., Loxitane.RTM.,
Serentil.RTM., Trilafon.RTM., Clozaril.RTM., Geodon.RTM.,
Risperdal.RTM., Seroquel.RTM., and Zyprexa.RTM.. [0222] 7.
Antidepressants: (Clinical use: treatment of depression, including
for acute depression as a substitute for electroconvulsive
therapy), utilizing perispinal administration without direct
intrathecal injection of the following): including, but not limited
to tricyclics, tetracyclics, trazadone, and SSRIs. [0223] 8.
Anticonvulsants: (Clinical use: treatment of seizures, particularly
status epilepticus, utilizing perispinal administration without
direct intrathecal injection of the following. In addition, please
note that these antiepileptic drugs may also be used for treatment
of other CNS disorders, such as psychoses and depression):
including, but not limited to, Valium.RTM., phenytoin, other
hydantoins, barbiturates, gabapentin, lamotrigine, carbamazepine,
topiramate, valproic acid, and zonisamide. [0224] 9. Opiates and
opioids: (Clinical use: treatment of pain, including acute pain
(e.g. labor and delivery, or field use following automobile
accident, etc.; or chronic pain, as a substitute for chronic
intrathecal drug delivery (e.g. as a substitute for chronic
intrathecal morphine utilizing an implanted pump), or as a
substitute for methadone maintenance treatment), utilizing
perispinal administration without direct intrathecal injection of
the following): including, but not limited to morphine, oxycodone,
other opiates and opioids, including oxycontin and methadone.
[0225] Perispinal extrathecal administration is distinguished from
intrathecal administration because extrathecal administration is
both safer (no dural puncture, therefore no risk of CSF leak; less
risk of hemorrhage; no risk of spinal cord traumatic injury; less
risk of hemorrhage and infection) and is more effective at
delivering the therapeutic molecule into the VVS. The dural
barrier, once crossed, will contain the therapeutic molecule within
the CSF. CSF flow from the spinal cord to the brain is slow. In
contrast retrograde flow to the brain via the VVS is much more
rapid.
[0226] For the purposes of this discussion, "perispinal" means in
the anatomic vicinity of the spine, but outside of the intrathecal
space. For this discussion "anatomic vicinity" is generally defined
as within 10 centimeters, or functionally defined as in close
enough anatomic proximity to allow the therapeutic molecules of
consideration herein to reach therapeutic concentration when
administered directly to this area without necessitating direct
intrathecal delivery.
[0227] Perispinal administration for delivery of large molecules,
including biologics, cytokines, anti-cytokines, hormones or drugs
via the vertebral venous system, in a manner as outlined herein,
may be performed. The compounds could include interleukins,
cytokines, interferons, drugs, growth factors, VEGF inhibitors,
monoclonal antibodies, fusion proteins, anti-angiogenic agents,
chemotherapeutic agents, cytostatic agents, cancer therapeutics,
viral or other vectors for delivering gene therapy or other
therapeutic molecules for which delivery by perispinal
administration without direct intrathecal injection would be
beneficial.
[0228] One of the advantages of perispinal delivery into the
interspinous space is that administration is simplified. This route
is simple and safe. Hemorrhage due to the use of long or large bore
needles is minimized because perispinal administration, by the
subcutaneous route, requires only a short, narrow bore needle.
Time-consuming and difficult epidural injection is not necessary.
Local perispinal administration also has the advantage of providing
a depot of therapeutic medication in the surrounding tissue, which
will provide therapeutic levels of medication to the treatment site
for a prolonged period of time. This decreases the necessity for
another injection of medication. Additionally, administering
medication locally limits the exposure of the medication to the
systemic circulation, thereby decreasing renal and hepatic
elimination of the medication, and decreasing exposure of the
medication to systemic metabolism. All of these factors tend to
increase the therapeutic half-life of the administered large
molecule. Taken together, all of these forms of perispinal
administration have significant clinical advantages over the
various forms of systemic administration customarily used to
deliver large molecules systemically. For example, intravenous
administration (as conventionally performed, by infusion into the
caval venous system) of infliximab is a systemic route of
administration, as defined herein, and is distinguished from
perispinal administration as a method to reach the brain
(predominantly via the VVS) as defined herein.
[0229] For the sake of this invention, the following definitions
also apply: perilesional is defined as in anatomic proximity to the
site of the pathologic process being treated; and peridural is
defined as in anatomic proximity to the dura of the spinal cord,
but specifically excluding intrathecal injection. The "interspinous
route" for the purposes of this patent, is defined as parenteral
injection through the skin in or near the midline, in the
interspace between two spinous processes.
[0230] This invention is distinguished from the prior art in a
variety of ways, including the use and description of novel and
useful new uses, methods of use, and concepts involving large
molecules, including: [0231] 1. Novel uses of perispinal
administration to enhance delivery of a large molecule to the
brain, the eye, the retina, the auditory apparatus, the cranial
nerves or the head; and [0232] 2. Novel methods of use of large
molecules; and [0233] 3. Novel concepts, including: [0234] a.
Perispinal (extrathecal) administration distinguished from systemic
forms of administration and intrathecal administration; [0235] b.
The use of the vertebral venous system to deliver large molecules
to the bone brain, the eye, the retina, the auditory apparatus, the
cranial nerves or the head; [0236] c. The use of physical maneuvers
to facilitate delivery of therapeutic molecules to the brain, the
eye, the retina, the auditory apparatus, the cranial nerves or the
head; [0237] d. The use of physical positioning to influence the
direction of venous flow within the vertebral venous system and
thereby deliver therapeutic molecules to the brain, the eye, the
retina, the auditory apparatus, the cranial nerves or the head;
[0238] e. The use of retrograde venous perfusion to deliver
therapeutic molecules to the brain, the eye, the retina, the
auditory apparatus, the cranial nerves or the head; [0239] f. The
use of retrograde venous perfusion via the vertebral venous system
to facilitate delivery of therapeutic molecules to the brain, the
eye, the retina, the auditory apparatus, the cranial nerves or the
head; [0240] g. The use of the vertebral venous system as a "back
door" to facilitate delivery of therapeutic molecules to the brain,
the eye, the retina, the auditory apparatus, the cranial nerves or
the head; [0241] h. The use of perispinal administration to
introduce a large molecule into the vertebral venous system; [0242]
i. The use of perispinal administration to efficiently deliver
large molecules to the brain, the eye, the retina, the auditory
apparatus, the cranial nerves or the head.
[0243] The same methods described for the named large molecules
(such as pegfilgrastim) of this invention also apply to other large
molecules with a molecular weight of 2,000 daltons or greater,
which may be given by perispinal administration.
[0244] A latitude of modification, change, and substitution is
intended in the foregoing disclosure, and in some instances, some
features of the invention will be employed without a corresponding
use of other features. Accordingly, it is appropriate that the
appended claims be construed broadly and in a manner consistent
with the spirit and scope of the invention herein.
(Experimental results compiled by the inventor illustrating the
efficacy of perispinal administration of a biologic are described
below. More specifically, these results illustrate the ability of
interspinous injection to lead to delivery of a biologic to the
VVS, and thereafter to the brain, utilizing the methods of the
present invention).
Experimental Results
[0245] An IRB-approved clinical trial utilizing perispinal
etanercept for treatment of Alzheimer's Disease was begun by the
inventor in 2004 and clinical data is available on the first 15
consecutive patients who completed more than three weeks of the
clinical trial, through Nov. 7, 2005, although the clinical trial
is ongoing. Data on the 6 month results is now available. A summary
of the study follows:
Patients
[0246] Patients residing in the community, who had previously been
diagnosed with Alzheimer's Disease by a board-certified neurologist
and were clinically declining despite treatment, were recruited,
without age restriction, for inclusion into a six month open-label
clinical trial utilizing perispinally administered etanercept.
Inclusion required that the patient meet the NINCDS-ADRDA Criteria
for probable Alzheimer's disease[1]; be accompanied by a reliable
caregiver; and have a previously performed MRI or CT scan
consistent with a primary diagnosis of AD. All recruited patients
also met the DSM-IV criteria for AD[2]. Patients were excluded if
they had any of the following: active infection, multiple sclerosis
(or any other demyelinating disorder), pregnancy, uncontrolled
diabetes mellitus, tuberculosis, history of lymphoma, or congestive
heart failure. In addition, female subjects who were premenopausal,
fertile, or not on acceptable birth control; and patients with a
white blood cell count <2500, hematocrit <30, or a platelet
count<100,000 were excluded. Patients with vascular dementia,
clinically significant neurologic disease other than Alzheimer's,
or a score greater than 4 on the modified Hachinski Ischemic Rating
Scale[3] were excluded. Additionally, to be eligible for study
inclusion, the dosage of all CNS-active medications was required to
be unchanged in the four weeks prior to study initiation and during
the entire course of the clinical trial.
Study Design
[0247] Patients received etanercept (Immunex Corp.) as a solution
in sterile water given by midline perispinal interspinous injection
in the posterior cervical area (as previously described[4])
utilizing a thin (27 gauge) needle, followed by head down
Trendelenburg positioning, once or twice per week, at a total dose
ranging from 25 mg to 50 mg per week (0.5-2 cc of solution) on an
open-label basis. The initial dose used was 25 mg once per week,
which was modified as needed. The trial was approved by a central
institutional review board. The eligible patients and their
responsible caregivers provided written informed consent.
Efficacy Variables
[0248] The primary efficacy variables for cognition were three
measures: the Alzheimer's Disease Assessment Scale-cognitive
subscale (ADAS-Cog); the Severe Impairment Battery; the Mini-Mental
State Examination (MMSE).
[0249] Patients were assessed at baseline (treatment day zero) and
monthly thereafter. All patients were assessed with the MMSE.
Patients with mild and moderate AD were assessed with ADAS-Cog.
Patients with severe dementia were assessed with the SIB.
[0250] Measures of safety included measurement of vital signs and
recording of adverse events.
Results
Study Population and Dosage
[0251] All data from all 15 patients who completed at least one
follow-up evaluation time-point were analyzed. All of these
patients completed the first six months of treatment. Treatment
response data were unavailable for two patients, in addition to the
above 15, who dropped out for non-medical reasons prior to their
first monthly evaluation; these two patients were excluded from
analysis. One patient whose dementia was borderline between
moderate and severe was assessed with both ADAS-Cog and SIB, in
addition to MMSE. The baseline characteristics of the 15 patient
study population are presented in Table 1. The average dosage for
the study cohort was 32.+-.12 mg per week (n=15), and the average
frequency of dosing was 1.07 times per week.
Statistical Analysis
[0252] The main efficacy analysis at 6 months is based on all 15
patients who have baseline and follow-up data.
[0253] The MMSE, ADAS-Cog, and the SIB are considered as the
primary outcome measures at the end of the three month follow-up
assessment. Mixed Model Linear Regression (MMLR) analyses were used
to assess improvement in disease over time, as evaluated by the
four outcome measures. In each analysis, time (baseline, 1, 2, 3,
4, 5 and 6 months) was entered as a fixed variable. The models were
also specified with random intercepts, as the participants in this
study varied across the spectrum of severity at baseline because
recruitment was not limited to a range of severity. Missing data
points are treated as missing and are not estimated; this was an
observed data analysis.
[0254] Data were analyzed using statistical analysis software SPSS
(Version 11.0.3 for Mac OS X, SPSS Inc., Chicago, Ill., USA), with
p<0.05 indicative of statistical significance.
Efficacy
[0255] The results of treatment through six months and the
statistical analysis are presented in Table 1.
TABLE-US-00001 TABLE 1 Summary of Mixed Model Linear Regression
(MMLR) results following initiation of perispinal etanercept. Mean
Mean Mean Mean Mean Mean Baseline change at change at change at
change at change at change at Regression Mean 1 month 2 months 3
months 4 months 5 months 6 months Analyses Measure (n) (SD) (SD)
(SD) (SD) (SD) (SD) (SD) Results MMSE (15) 18.2 -.29 +1.07 +1.87
+2.00 +1.93 +2.13 F (1.84) = 39.00, (8.8) (1.82) (2.01) (1.99)
(2.13) (2.34) (2.23) p < .001 ADAS-cog (11) 20.85 -4.28 -4.64
-4.67 -7.14* -4.52 -5.48 F (1.61) = 11.72, (10.5) (3.44) (4.36)
(5.97) (4.51) (4.80) (5.08) p < .002 SIB (5) 62.5 +4.67 +8.2
+11.75 +13.6 +13.0 +16.6 F (1.26) = 22.60, (28.05) (6.35) (3.56)
(6.45) (10.89) (13.69) (14.52) p < .001 Caption: Baseline raw
group mean and standard deviations are presented with the mean
change and SD (each participant compared to their respective
baseline performance) for the 6 subsequent follow-up months. Note:
For the ADAS-Cog, lower scores indicate clinical improvement. *Note
2: reduced n = 7 at this time point. SD = Standard Deviation
TABLE-US-00002 TABLE 2 Patient Characteristics, at baseline, prior
to perispinal etanercept treatment. Mean .+-. SD Range
Characteristic Age, in yrs. 76.7 .+-. 10.9 52, 94 Female, % (n) 60%
(9) -- Duration of symptoms, in mos. 43.1 .+-. 37.9 8, 120 ADAS-Cog
score (n = 11) 20.8 .+-. 10.5 7.3, 41 SIB score (n = 5) 62.5 .+-.
28.05 28, 92 MMSE score (n = 15) 18.2 .+-. 8.8 0, 29 Prior
Treatments: Memantine, % (n) 73% (11) -- Duration prior to
Etanercept, 10.6 .+-. 4.0 1.5, 15 in mos. Donepezil, % (n) 47% (7)
-- Duration prior to Etanercept, 44.7 .+-. 47.9 10, 120 in mos.
Rivastigmine, % (n) 27% (4) -- Duration prior to Etanercept, 5.6
.+-. 3.3 1, 8 in mos. Galantamine, % (n) 13% (2) -- Duration prior
to Etanercept, 40.5 .+-. 6.4 36, 45 in mos. Only 1 of the above, %
(n) 40% (6) -- Memantine + a cholineserase 60% (9) -- inhibitor, %
(n)
(End of Experimental Results).
PREFERRED EMBODIMENTS
[0256] In one preferred embodiment a patient with a clinical
disorder involving the brain, the retina, the eye, the cranial
nerves or hearing is treated by a perispinal injection of a large
molecule, in a therapeutically effective dose, delivered by midline
transcutaneous injection overlying the spine in the lower posterior
neck area, with the patient sitting and head flexed forward, with
immediate placement of the patient in the prone position with the
plane of the examination table directed head downward about 15
degrees after the injection, and maintenance of the patient in this
modified Trendelenburg prone position for several minutes after
injection, in order to deliver the large molecule to the brain, the
retina, the eye, the cranial nerves or the auditory apparatus via
the vertebral venous system, with the dose repeated as a form of
chronic therapy at intervals as often as twice per week to as
little as once per three months.
[0257] In another preferred embodiment an individual with a
clinical disorder involving the eye or retina, who desires to
achieve improved vision or to prevent visual loss, is treated by a
perispinal injection of etanercept using a 25 mg dose in solution,
delivered by midline transcutaneous injection overlying the spine
in the lower posterior neck area, with the patient sitting and head
flexed forward, with immediate placement of the patient in the
prone position with the plane of the examination table directed
head downward about 15 degrees after the injection, and maintenance
of the patient in this modified Trendelenburg prone position for
several minutes after injection, as either a single dose, or with
doses repeated as often as once per week.
[0258] In another preferred embodiment injection of a large
molecule to the perispinal area is accomplished by percutaneous
injection into the anatomic area between two adjacent spinous
processes ("the interspinous space").
[0259] In another preferred embodiment interspinous injection is
accomplished by injection through the skin
Clinical Disorders
[0260] Patients with the following clinical disorders, or in the
following clinical situations, among others, will benefit from
treatment with large molecules delivered by the perispinal route
without direct intrathecal injection:
Macular Degeneration.
[0261] This category includes both "wet" or "dry" macular
degeneration, both of which involve excess TNF and/or the
participation of TNF-mediated inflammatory or degenerative pathways
in their pathogenesis. Treatment of patients with these disorders
with perispinal etanercept leads to visual improvement and/or
slowing of disease progression. Chronic treatment regimens are
necessary utilizing perispinal etanercept. Certolizumab pegol or
golimumab may be used in a manner which is similar to that of
etanercept, except that due to their longer half-life less frequent
administration, compared to etanercept, is necessary. Etanercept,
golimumab, or certolizumab pegol may be administered concurrently
with memantine (delivered orally) to further reduce retinal
inflammation or optic nerve damage. Also soluble TNF receptor type
1, and pegylated soluble TNF receptor type 1 may be administered by
perispinal administration for treatment of this disorder.
Pegapanib, ranibizumab, and bevacizumab (Avastin.TM., Genentech), a
recombinant humanized monoclonal IgG1 antibody that binds to and
inhibits the biologic activity of human vascular endothelial growth
factor (VEGF), may also be administered by perispinal
administration without direct intrathecal injection for both the
treatment or prevention of macular degeneration and/or
neovascularization and thereby produce visual improvement or
prevention or delay of future visual loss. Additionally these
disorders are known to involve IL-1. Therefore treatment of these
disorders with an IL-1 antagonist, such as IL-1 RA (Kineret) or
IL-1 Trap administered by perispinal delivery so that a
therapeutically effective dose of the IL-1 antagonist reaches the
vertebral venous system and thenceforth the retina, delivered
utilizing a chronic treatment regimen, is an alternative treatment.
Each of these molecules will need to be delivered on a chronic
basis to decrease the inflammatory response which is responsible
for neuronal damage in these conditions and thereby produce
clinical improvement.
Diabetic Retinopathy.
[0262] This condition involves excess TNF and/or the participation
of TNF-mediated inflammatory or degenerative pathways in its
pathogenesis. Treatment of patients with this disorder with
perispinal etanercept leads to visual improvement and/or slowing of
disease progression. Chronic treatment regimens are necessary
utilizing perispinal etanercept. Golimumab may be used in a manner
which is similar to that of etanercept, except that due to its
longer half-life less frequent administration, compared to
etanercept, will be necessary. Also soluble TNF receptor type 1,
and pegylated soluble TNF receptor type 1 may be administered by
perispinal administration for treatment of this disorder.
Pegapanib, ranibizumab, and bevacizumab (Avastin.TM., Genentech), a
recombinant humanized monoclonal IgG1 antibody that binds to and
inhibits the biologic activity of human vascular endothelial growth
factor (VEGF), may also be administered by perispinal
administration for both the treatment or prevention of diabetic
retinopathy and/or neovascularization and thereby produce visual
improvement or prevention or delay of future visual loss.
Additionally these disorders are known to involve IL-1. Therefore
treatment of this disorder with an IL-1 antagonist, such as IL-1 RA
(Kineret) or IL-1 Trap administered by perispinal delivery so that
a therapeutically effective dose of the IL-1 antagonist reaches the
vertebral venous system and thenceforth the retina, delivered
utilizing a chronic treatment regimen, is an alternative treatment.
Each of these molecules will need to be delivered on a chronic
basis to decrease the inflammatory response which is responsible
for neuronal damage in these conditions and thereby produce
clinical improvement.
Glaucoma.
[0263] This condition involves excess TNF and/or the participation
of TNF-mediated inflammatory or degenerative pathways in its
pathogenesis. Treatment of patients with this disorder with
perispinal etanercept leads to visual improvement and/or slowing of
disease progression. Chronic treatment regimens are necessary
utilizing perispinal etanercept. Golimumab may be used in a manner
which is similar to that of etanercept, except that due to its
longer half-life less frequent administration, compared to
etanercept, will be necessary. Also soluble TNF receptor type 1,
and pegylated soluble TNF receptor type 1 may be administered by
perispinal administration for treatment of this disorder.
Etanercept or golimumab may be administered concurrently with
memantine (delivered orally) to further reduce retinal inflammation
or optic nerve damage. Additionally these disorders are known to
involve IL-1. Therefore treatment of this disorder with an IL-1
antagonist, such as IL-1 RA (Kineret) or IL-1 Trap administered by
perispinal delivery so that a therapeutically effective dose of the
IL-1 antagonist reaches the vertebral venous system and thenceforth
the retina, delivered utilizing a chronic treatment regimen, is an
alternative treatment. Each of these molecules will need to be
delivered on a chronic basis to decrease the inflammatory response
which is responsible for neuronal damage in these conditions and
thereby produce clinical improvement.
Retinitis Pigmentosa.
[0264] This condition involves excess TNF and/or the participation
of TNF-mediated inflammatory or degenerative pathways in its
pathogenesis. Treatment of patients with this disorder with
perispinal etanercept leads to visual improvement and/or slowing of
disease progression. Chronic treatment regimens are necessary
utilizing perispinal etanercept. Golimumab may be used in a manner
which is similar to that of etanercept, except that due to its
longer half-life less frequent administration, compared to
etanercept, will be necessary. Also soluble TNF receptor type 1,
and pegylated soluble TNF receptor type 1, or Certolizumab pegol
may be administered by perispinal administration for treatment of
this disorder. Etanercept or golimumab may be administered
concurrently with memantine (delivered orally) to further reduce
retinal inflammation or optic nerve damage. Additionally these
disorders are known to involve IL-1. Therefore treatment of this
disorder with an IL-1 antagonist, such as IL-1 RA (Kineret) or IL-1
Trap administered by perispinal delivery so that a therapeutically
effective dose of the IL-1 antagonist reaches the vertebral venous
system and thenceforth the retina, delivered utilizing a chronic
treatment regimen, is an alternative treatment. Each of these
molecules will need to be delivered on a chronic basis to decrease
the inflammatory response which is responsible for neuronal damage
in these conditions and thereby produce clinical improvement.
Dementia.
[0265] This category includes, but is not limited to Alzheimer's
Disease, amnestic mild cognitive impairment, vascular dementia, and
mixed dementia. The inventor has clinical experience utilizing
etanercept delivered by perispinal extrathecal administration
demonstrating clinical benefit for each of these conditions. Humans
with these disorders are amenable to treatment utilizing perispinal
administration without direct intrathecal injection of large
molecules, including but not limited to etanercept, golimumab,
certolizumab pegol and other anti-TNF molecules (as illustrated by
the experimental results included herein), MRA (Roche, Chugai), a
humanized anti-IL-6 receptor monoclonal antibody; anti-IL-1
molecules; immune globulin (such as IVIG, Baxter, being a mixture
of immune globulins, including anti-amyloid antibodies) and other
large molecules with immune activity. Golimumab is used by
perispinal administration at a dose ranging from 5 mg to 100 mg,
with a dosing interval from weekly to once per three months. The
usual starting dose of golimumab for a human with dementia such as
Alzheimer's Disease is 10 mg to 25 mg once per two weeks, with
dosage titrated as needed within the above dosing guidelines.
Malignant Tumors Metastatic to the Spine:
[0266] Malignant tumors metastatic to the spine may be treated by
the use of biologics delivered via the VVS. Access to the VVS may
be accomplished by perispinal administration, in the general manner
as described herein for etanercept. There is also experimental
evidence that both pro-inflammatory cytokines and their antagonists
can be effective in the treatment of malignancies. This has been
demonstrated most clearly with TNF, where high doses have been
found to lead to tumor death; and, also with TNF blockers that
demonstrate a therapeutic benefit in treating certain malignancies.
This apparent paradox is explained by dose effects wherein a high
dosage of TNF may lead to tumor death, whereas a low dosage may be
tumor promoting. Therefore this invention includes any of the
following molecules used individually: etanercept, golimumab,
certolizumab pegol or pegsunercept; and, additionally, includes
other biologic TNF antagonists, including infliximab, when
delivered by perispinal extrathecal administration. The dosage of
etanercept for this application ranges from 25 mg to 100 mg; the
dosage of golimumab for this application ranges from 10 mg to 200
mg, and will most often range between 25 mg and 100 mg.
Malignant Intracranial Tumors.
[0267] This category includes both primary brain tumors, such as
glioblastoma multiforme and tumors metastatic to the brain, all of
which involve excess VEGF and/or the participation of VEGF-mediated
angiogenesis, or immune mechanisms in their pathogenesis. Treatment
of patients with these disorders with perispinal administration
without direct intrathecal injection of a large molecule which
inhibits VEGF; or which is directly toxic to a tumor, including,
but not limited to monoclonal antibodies, or monclonal
antibody-antitumor conjugates; or which otherwise positively
affects immune mechanisms; including, but not limited to such large
molecules as etanercept, certolizumab pegol, IL-1 Trap,
Kineret.RTM., bevacizumab, pegaptanib, ranibizumab, Zevalin.RTM.,
Mylotarg.RTM., Campath.RTM., HumaSpect.RTM., panitumumab,
trastuzumab, Ontak.RTM., Simulect.RTM., Zenapax.RTM., leads to
reduced tumor growth, tumor death, and/or slowing of disease
progression. CNS lymphomas and other CNS malignancies may be
treated by perispinal administration without direct intrathecal
injection of rituximab, temozolomide, yttrium-90 ibritummomab
tiuxetan, iodine-131 tositumomab, epratuzumab, alemtuzumab, or
natalizumab.
[0268] Chronic or recurrent treatment regimens may be necessary to
deliver these large molecules to the intracranial tumor via
perispinal administration without direct intrathecal
administration. Avoidance of intrathecal use is safer, has fewer
side effects, avoids CSF leak from a dural tear, and eliminates the
need for chronic intrathecal delivery systems, such as pumps. Small
molecules may also be administered by perispinal delivery without
direct intrathecal injection as discussed in a preceding section.
Perispinal delivery of small molecules allows the achievement of a
higher concentration of the small molecule in the brain and
therefore in an intracranial malignant tumor. This is particularly
advantageous for small molecules which have therapeutic activity
for the treatment of cancer, such as a receptor tyrosine kinase
inhibitor. Erlotinib is a small molecule epidermal growth factor
receptor (EGFR) inhibitor which is conventionally used for
treatment of non-small cell lung cancer (NSCLC). Gefitinib is
another tyrosine kinase inhibitor which may be formulated in
solution and therefore delivered by perispinal administration. This
invention includes the use of erlotinib in solution, gefitinib in
solution, or an erlotinib or gefitinib derivative or other receptor
tyrosine kinase inhibitors, given by perispinal administration for
treatment of intracranial malignant tumors, including lung cancer
metastatic to the brain, or metastases to the brain of other
malignant tumors which overexpress EGFR, or for treatment of
primary brain tumors, including glioblastoma multiforme. Receptor
tyrosine kinase is a protein product of the EGFR gene. Inhibition
of EGFR-associated tyrosine kinase is a method of treating solid
tumors, including NSCLC, and perispinal administration of these
agents is a method of the present invention to increase delivery of
these agents to intracranial tumors. Erlotinib has a MW of 429.
Perispinal administration of the molecules of the present invention
leading to delivery of a therapeutically effective amount of said
molecule to the brain, the eye, or an intracranial tumor is
distinguished from the systemic administration of said
molecules.
Multiple Sclerosis.
[0269] This immune-mediated disease of the brain is conventionally
treated by systemic administration of Copaxone.RTM. (glatiramer
acetate), or interferons, including Avonex.RTM., Rebif.RTM., and
Betaseron.RTM.. Perispinal administration of these molecules, and
other large molecules, including, but not limited to, rituximab,
MRA, Intron A.RTM., PEG-Intron.RTM., Infergen.RTM., and
Actimmune.RTM. will allow therapeutically effective amounts of
these large molecules to reach to brain of a human with this
disorder, thereby leading to clinical improvement or a decrease in
the rate of disease progression.
Hearing Loss.
[0270] Hearing loss occurs in humans in many forms. Hearing is
essential to the normal conduct of one's daily activities and
people with impaired hearing have many difficulties. Hearing loss
can date from birth; it can be acquired later in life; or it can be
the result of trauma, accident, disease, or a toxic effect of a
medication. It can be genetic, either as a solitary disorder or as
part of a complex syndrome. Hearing loss is one of the most common
chronic neurological impairments, estimated to affect about 4
percent of those under 45 in the United States, and about 29
percent of those 65 years or older. [0271] As defined herein, the
neuronal auditory apparatus includes the cochlea, the auditory
division of the eighth cranial nerve, and the central auditory
pathways. Sensorineural hearing loss is one particular category of
hearing loss and is caused by lesions of the cochlea and/or the
auditory division of the eighth cranial nerve. Prior to this
invention, treatment of this condition was primarily limited to the
use of hearing aids. [0272] The pathogenetic mechanism of most
forms of hearing loss has yet to be fully defined. The subjects of
this patent include central hearing loss due to lesions of the
central auditory pathway; sensorineural hearing loss; sudden
hearing loss; autoimmune hearing loss; presbycusis; idiopathic
hearing loss; and other forms of hearing loss which are not thought
to be primarily due to disorders of conduction (such as a ruptured
tympanic membrane). [0273] Humans react to sounds that are
transduced into neurally conducted impulses through the action of
neuroepithelial cells (hair cells) and spiral ganglion cells
(neurons) in the inner ear. These impulses are transmitted along
the cochlear division of the eighth cranial nerve into the
brainstem and the central auditory pathways.
[0274] Presbycusis, or age-related hearing loss, is a type of
deafness which affects one-third of the population over the age of
75. Presbycusis is known to be associated with neuronal damage,
including loss of neuroepithelial (hair) cells and associated
neurons (see Schuknecht reference). The exact mechanism of
presbycusis is unknown, and has long been thought to be
multifactorial. Inflammation is not widely recognized as a
significant factor in the pathogenesis of presbycusis. Yet a
previous study did suggest that genes encoded by the major
histocompatibility complex (MHC) had a role in certain hearing
disorders. (Bernstein, Acta Otolaryngol 1996 September;
116(5):666-71). The MHC is known to be central to the immune
response and inflammation. Normal hearing is dependant upon proper
neuronal function, and may be altered by autoimmune disorders or
other types of inflammation. The neuronal auditory apparatus is
protected by the blood-brain barrier. Therefore delivery of large
molecules for therapeutic purposes by the systemic route is
inhibited by the BBB. Delivery of large molecules, in particular
anti-TNF biologics, including golimumab and others, or other
biologics which reduce inflammation, by perispinal administration,
as illustrated herein, is an effective way to treat various types
of hearing loss, including sensorineural hearing loss and
presbycusis.
Neuropsychiatric Disorders.
[0275] Psychiatric disorders which have a biological basis, such as
depression and schizophrenia, can be treated by the methods of the
present invention. In particular, humans with these disorders are
amenable to treatment utilizing perispinal administration without
direct intrathecal injection of large molecules, including but not
limited to anti-TNF molecules, including golimumab and others (as
illustrated by the experimental results included herein), MRA
(Roche, Chugai), a humanized anti-IL-6 receptor monoclonal
antibody; anti-IL-1 molecules; and other large molecules with
immune activity.
Brain Disorders.
[0276] Brain disorders which have a biological basis, such as
seizure disorders, Huntington's Chorea, Parkinson's Disease, and
other brain disorders, can be treated by the methods of the present
invention. In particular, humans with these disorders are amenable
to treatment utilizing perispinal administration without direct
intrathecal injection of large molecules, including but not limited
to anti-TNF molecules, including golimumab and others (as
illustrated by the experimental results included herein), MRA
(Roche, Chugai), a humanized anti-IL-6 receptor monoclonal
antibody; anti-IL-1 molecules; and other large molecules with
immune activity.
Disc-Related Pain, Including Low Back Pain, Cervical Radiculopathy,
Discogenic Pain, Sciatica, and Pain Associated with Degenerative
Disc Disease.
[0277] The author has considerable experience utilizing perispinal
etanercept for the treatment of low back pain, discogenic pain,
cervical radiculopathy, sciatica and related disorders which has
established the efficacy of this novel method of treatment.
Certolizumab pegol and golimumab given to a human or other mammal
by perispinal administration is also effective for treating these
disorders.
Dosages and Routes of Administration
[0278] The therapeutically effective dosage of a large molecule
used for perispinal administration will in general be 10% to 100%
of the dosage used as a single dose for systemic administration.
This dosage used for systemic administration is well known by those
skilled in the art as it is specified in the FDA approved
literature which accompanies each of these biologics, since each is
FDA approved for other clinical uses. For example, if the usual
dose when administered systemically is 50 mg, then the dose used
for perispinal administration will usually be between 5 mg and 50
mg.
[0279] Golimumab may be administered to the perispinal area by
interspinous injection at a dose of 5 mg to 100 mg given from once
per week to once per 3 months. Starting doses of 10 mg-25 mg every
other week are given for treatment of dementia.
[0280] Etanercept may be administered in the perispinal area
subcutaneously in the human and the dosage level is in the range of
10 mg to 100 mg per dose, with dosage intervals as short as one
day.
[0281] Pegaptanib may be administered perispinally in a
therapeutically effective dose. The dosage of pegaptanib may vary
from 0.2 mg to 10 mg per dose.
[0282] Ranibizumab may be administered in a therapeutically
effective dose in the same ways as detailed for etanercept. The
dosage of ranibizumb may vary from 100 micrograms to 3000
micrograms. For treating ocular neovascularization the most common
dosage regimen is 800 micrograms of ranibizumab administered by
perispinal injection every 28 days for four doses.
[0283] It will be appreciated by one of skill in the art that
appropriate dosages of the compounds, and compositions comprising
the compounds, can vary from patient to patient. The determination
of the optimal dosage will generally involve the balancing of the
level of therapeutic benefit against any risk or deleterious side
effects. The selected dosage level will depend on a variety of
factors including, but not limited to, the activity of the
particular compound, the route of administration, the time of
administration, the rate of excretion of the compound, the duration
of the treatment, other drugs, compounds, and/or materials used in
combination, the severity of the condition, and the species, sex,
age, weight, condition, general health, and prior medical history
of the patient. The amount of compound and route of administration
will ultimately be at the discretion of the physician,
veterinarian, or clinician, although generally the dosage will be
selected to achieve local concentrations at the site of action
which achieve the desired effect without causing substantial
harmful or deleterious side-effects.
[0284] A latitude of modification, change, and substitution is
intended in the foregoing disclosure, and in some instances, some
features of the invention will be employed without a corresponding
use of other features. Accordingly, it is appropriate that the
appended claims be construed broadly and in a manner consistent
with the spirit and scope of the invention herein.
[0285] Definitions provided herein are not intended to be limiting
from the meaning commonly understood by one of skill in the art
unless indicated otherwise.
[0286] The inventions illustratively described herein may suitably
be practiced in the absence of any element or elements, limitation
or limitations, not specifically disclosed herein. Thus, for
example, the terms "comprising", "including," containing", etc.
shall be read expansively and without limitation. Additionally, the
terms and expressions employed herein have been used as terms of
description and not of limitation, and there is no intention in the
use of such terms and expressions of excluding any equivalents of
the features shown and described or portions thereof, but it is
recognized that various modifications are possible within the scope
of the invention claimed. Thus, it should be understood that
although the present invention has been specifically disclosed by
preferred embodiments and optional features, modification and
variation of the inventions embodied therein herein disclosed may
be resorted to by those skilled in the art, and that such
modifications and variations are considered to be within the scope
of this invention.
6. ADVANTAGES OF THE PRESENT INVENTION
[0287] Accordingly, an advantage of the present invention is that
it provides for the delivery of a large molecule to the vertebral
venous system and thenceforth to the brain, the retina, the eye,
the cranial nerves and the auditory apparatus as a new biologic
treatment of humans with a clinical disorder of the brain, the
retina, the eye, the cranial nerves, or hearing; such that the use
of the biologic will result in clinical improvement, or will slow
progression of the underlying pathologic process.
[0288] Accordingly, an advantage of the present invention is that
it provides for the delivery of golimumab to the vertebral venous
system and thenceforth to the brain, the retina, the eye, the
cranial nerves and the auditory apparatus as a new biologic
treatment of humans with a clinical disorder of the brain, the
retina, the eye, the cranial nerves, or hearing; such that the use
of golimumab will result in clinical improvement, or will slow
progression of the underlying pathologic process.
[0289] Another advantage of the present invention is that it
provides for a biologic delivered by perispinal administration,
thereby delivering the biologic into the vertebral venous system
and thenceforth the brain, the retina, the eye, the auditory
apparatus or the cranial nerves, which, when compared to systemic
administration, produces one or more of the following: greater
efficacy; more rapid onset; longer duration of action; improved
delivery to the CNS; or fewer side effects.
[0290] Another advantage of the present invention is that it
provides for one of a group of biologics, as specified herein,
which affect neuronal or immune function, delivered by retrograde
venous flow through the vertebral venous system into the cranial
venous system, thereby facilitating delivery of the biologic to the
brain, the retina, the eye, the cranial nerves and the auditory
apparatus for therapeutic purposes.
[0291] Accordingly, an advantage of the present invention is that
it provides for the delivery of erlotinib to the vertebral venous
system and thenceforth to a malignant intracranial tumor as a new
biologic treatment of humans; such that the use of erlotinib will
result in clinical improvement, or will slow progression of the
cancer.
[0292] A latitude of modification, change, and substitution is
intended in the foregoing disclosure, and in some instances, some
features of the invention will be employed without a corresponding
use of other features. Accordingly, it is appropriate that the
appended claims be construed broadly and in a manner consistent
with the spirit and scope of the invention herein.
* * * * *