U.S. patent application number 09/760362 was filed with the patent office on 2002-04-25 for novel treatment for eye disease.
Invention is credited to Chen, James C..
Application Number | 20020049247 09/760362 |
Document ID | / |
Family ID | 22641231 |
Filed Date | 2002-04-25 |
United States Patent
Application |
20020049247 |
Kind Code |
A1 |
Chen, James C. |
April 25, 2002 |
Novel treatment for eye disease
Abstract
This invention discloses methods, kits, and instructions to
treat neovasculature diseases of the eye through the administration
of a targeted photosensitizing agent and subsequent exposure to
light of specific wavelength sufficient to photoactivate
photosensitizing agent. The photosensitizing agent is bound to a
composition that mediates site specific delivery to a
neovasculature target tissue of a therapeutically effective amount
of a photosensitizing agent that is activated by a relatively low
fluence rate of light over a prolonged period of time. Diseases
treatable under this invention, include: diabetic retinopathy;
macular degeneration; and malignant uveal melanomas.
Inventors: |
Chen, James C.; (Bellevue,
WA) |
Correspondence
Address: |
Stephanie L. Seidman
Heller Ehrman White & McAuliffe, LLP
6th Floor
4350 La Jolla Village Drive
San Diego
CA
92122-1246
US
|
Family ID: |
22641231 |
Appl. No.: |
09/760362 |
Filed: |
January 12, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60175689 |
Jan 12, 2000 |
|
|
|
Current U.S.
Class: |
514/410 ;
604/20 |
Current CPC
Class: |
A61K 41/0076 20130101;
A61K 41/0057 20130101; A61K 47/6847 20170801; A61K 47/62 20170801;
A61K 47/6843 20170801; A61P 27/02 20180101; A61P 35/00 20180101;
A61P 3/10 20180101; A61K 41/0071 20130101; A61P 9/00 20180101; Y10S
514/912 20130101 |
Class at
Publication: |
514/410 ;
604/20 |
International
Class: |
A61K 031/409; A61N
001/30 |
Claims
The invention claimed is:
1. A method to treat neovascular disease of the eye, comprising:
administering a targeted photosensitizing compound which
selectively binds to abnormal endothelium that lines or composes
neovasculature tissue; and illuminating the neovasculature tissue
with light for a period of time sufficient to activate the
photosensitizing compound thereby causing damage to neovasculature
tissue.
2. The method of claim 1, wherein said light is non-laser
light.
3. The method of claim 1, wherein said light is laser light.
4. The method of claim 1, wherein the neovasculature tissue is
present in retina, choroid or both.
5. The method of claim 1, wherein the treated neovascular disease
is diabetic retinopathy.
6. The method of claim 1, wherein the treated neovascular disease
is macular degeneration.
7. The method of claim 1, wherein the treated neovascular tissue
arises from tumors of the eye.
8. The method of claim 1, wherein said tumors are benign.
9. The method of claim 1, wherein said tumors are malignant.
10. The method of claim 9, wherein said tumors are malignant uveal
melanomas.
11. The method of claim 1, wherein the targeted photosensitizing
compound is bound to a first component of a bindable pair and
wherein a second component of the bindable pair is selected from
the group consisting of: receptor present on abnormal endothelium;
ligand bindable to receptor present on abnormal endothelium;
antigen present on abnormal endothelium; and antibody bindable to
antigen present on abnormal endothelium.
12. The method of claim 11, wherein the targeted photosensitizing
compound is incorporated into a liposomal preparation.
13. The method of claim 11, wherein the ligand is selected from the
group consisting of: the ED-B domain of fibronectin; antibody
specifically elicited to ED-B domain of fibronectin; VEGF; VEGF
receptor; and .alpha..nu..beta.3 integrin receptor.
14. The method of claim 1, wherein the targeted photosensitizing
compound is bound to a receptor composition that mimics a receptor
present on abnormal endothelium.
15. The method of claim 14, wherein the targeted photosensitizing
compound is incorporated into a liposomal preparation.
16. The method of claim 1, wherein the targeted photosensitizing
compound is bound to a bi-specific antibody construct that further
comprises both a ligand component and a receptor component.
17. The method of claim 16, wherein the targeted photosensitizing
compound is incorporated into a liposomal preparation.
18. The method of claim 1, wherein the photosensitized
neovasculature is illuminated for at least 4 minutes.
19. The method of claim 1, wherein the photosensitized
neovasculature is illuminated for at least 20 minutes.
20. The method of claim 1, wherein the photosensitized
neovasculature is illuminated for at least 1 hour.
21. The method of claim 1, wherein the photosensitized
neovasculature is illuminated for at least 24 hours.
22. The method of claim 1, wherein the neovasculature tissue is
treated with a total fluence of light irradiation from between
about 240 J/cm.sup.2 to about 900 J/cm.sup.2.
23. The method of claim 1, wherein the non-laser light source is a
light emitting diode.
24. The method of claim 1, wherein the non-laser light source is
ambient light.
25. A method to treat neovascular disease of the eye, comprising:
administering a first targeted photosensitizing compound which
selectively binds to a first targeted tissue; and administering a
second targeted photosensitizing compound which selectively binds
to a second targeted tissue; and illuminating the first and second
targeted tissues with non-laser light for a period of time
sufficient to activate said first and second photosensitizing
compounds thereby causing damage to said first and second targeted
tissue.
26. The method of claim 25, wherein said first targeted tissues is
abnormal endothelium that lines or composes neovasculature tissue;
and said second targeted tissue is a tumor antigen.
27. The method of claim 26, wherein said first targeted
photosensitizing compound comprises a ligand selected from the
group consisting of: the ED-B domain of fibronectin; antibody
specifically elicited to EDB domain of fibronectin; VEGF; VEGF
receptor; and .alpha..nu..beta.3 integrin receptor.
28. A kit to treat neovascular disease of the eye, comprising a
targeted photosensitizing compound and instructions teaching a
method according to claim 1.
29. A kit according to claim 28 wherein the targeted
photosensitizing compound binds to a first component of a bindable
pair and wherein a second component of the bindable pair is
selected from the group consisting of: receptor present on abnormal
endothelium; ligand bindable to receptor present on abnormal
endothelium; antigen present on abnormal endothelium; and antibody
bindable to antigen present on abnormal endothelium.
30. A kit according to claim 29, wherein the targeted
photosensitizing compound is incorporated into a liposomal
preparation.
31. A kit according to claim 29, wherein the ligand is selected
from the group consisting of: the ED-B domain of fibronectin;
antibody specifically elicited to ED-B domain of fibronectin; VEGF;
VEGF receptor; and .alpha..nu..beta.3 integrin receptor.
32. A kit according to claim 28, wherein the targeted
photosensitizing compound binds to a receptor composition that
mimics a receptor present on abnormal endothelium.
33. A kit according to claim 32, wherein the targeted
photosensitizing compound is incorporated into a liposomal
preparation.
34. A kit according to claim 28, wherein the targeted
photosensitizing compound binds to a bi-specific antibody construct
that further comprises both a ligand component and a receptor
component.
35. A kit according to claim 34, wherein the targeted
photosensitizing compound is incorporated into a liposomal
preparation.
36. A method of instructing a person to treat neovascular disease
of the eye, comprising instructing a person to conduct a method
according to claim 1.
37. A method of instructing a person to treat neovascular disease
of the eye, comprising instructing a person in the use of the kit
of claim 28.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. application Ser.
No. 60/175,689, filed Jan. 12, 2000. This application is also
related to the PCT application entitled "Novel Treatment for Eye
Disease," Inventor James C. Chen, attorney docket number
398032000940, filed on even date herewith. Each of these
applications is incorporated by reference herein in its entirety as
if fully set forth below.
TECHNICAL FIELD
[0002] This invention relates generally to the field of medicine
and pharmacotherapeutics with photosensitizing agents or other
energy activated agents. Specifically, this invention relates to
kits and methods useful for the treatment of neovascular diseases
of the eye. The invention involves the site specific delivery to a
neovasculature target tissue of a therapeutically effective amount
of a photosensitizing agent that is activated by a relatively low
fluence rate of light over a prolonged period of time.
BACKGROUND ART
[0003] Neovascular diseases of the eye include diabetic
retinopathy, age-related macular degeneration and neovasculature
growth induced by angiogenic factors or resulting from tumor cells,
themselves. Diabetic retinopathy is characterized by a number and
variety of microvascular changes which can result ultimately in
adverse visual changes and vision loss. In many cases the
microvascular changes are due to or associated with upregulation of
angiogenesis receptors and factors or ligands which lead to new
vessel formation, changes in vascular permeability, and possibly
other alterations in vessel morphology. These changes may lead to
hemorrhage, edema, ischemia, and other problems resulting in vision
dysfunction (see: Aiello et al., Diabetes Care, 21:143-156,
1998).
[0004] Treatments for the various forms of, and problems associated
with, diabetic retinopathy include laser photocoagulation,
vitrectomy, cryotherapy, and membranotomy. All of these clinical
therapies and procedures are associated with problems and side
effects. For example, the side effects and complications related to
panretinal laser photocoagulation, the most common present
treatment for diabetic retinopathy, include: decreased visual
acuity, increased macular edema, transient pain, exudative retinal
detachment, and inadvertent foveolar bums.
[0005] Age-related macular degeneration ("AMD") is the leading
cause of blindness in the United States among individuals 65 or
older. One form of AMD is characterized by formation of choroidal
neovessels which can lead to a number of pathologic conditions
resulting in visual dysfunction and loss. As with diabetic
retinopathy, angiogenesis plays a key role in the formation of
these neovessels. The proliferation of choroidal neovessels
associated with AMD can contribute to irreversible damage of
photoreceptors. Thus, current treatment of AMD, like that of
diabetic retinopathy, involves the use of laser photocoagulation.
However, because photocoagulation relies upon the gross thermal
destruction of the choroidal neovascular tissue, damage to the
retina and surrounding choroidal tissue often results. Furthermore,
recurrences after photocoagulation therapy are common. (see:
Schmidt-Erfurth et al., Greafe's Arch Clin Exp Opthamol,
236:365-374, 1998).
[0006] As an alternative to photocoagulation, photodynamic therapy
has been proposed as a means of treating this form of AMD (see:
Strong et al., "Vision through photodynamic therapy of the eye,"
U.S. Patent Nos. 5,756,541 and 5,910,510; and Mori et al.,
"Photochemotherapeutical obstruction of newly-formed blood
vessels," U.S. Patent No. 5,6333,275). Photodynamic therapy
("PDT"), as taught in this prior art, is a two-step treatment
process. PDT is performed by first administering a photosensitive
compound systemically or topically, followed by illumination of the
treatment site at a wavelength or waveband of light from a laser
which closely matches the absorption spectra of the
photosensitizer. In doing so, singlet oxygen and other reactive
species are generated leading to a number of biological effects
resulting in damage to the endothelial membranes and ultimately to
clotting of the neovasculature.
[0007] Although this form of PDT represents an improvement over
photocoagulation, clinical experience has established that the
therapy must be repeated on a regular basis, typically every 3
months due to regrowth of the vessels (see: Schmidt-Erfurth et
al.). The regrowth is believed to be due to upregulation of
angiogenic factors and/or receptors secondary to the relative
ischemia caused by the PDT treatment as outlined in the prior art.
Clearly there is a need for a therapy which reduces the number of
treatments which probably need to be performed for the rest of the
patient's life.
[0008] In addition to neovascular tissue formation associated with
diabetic retinopathy and age-related macular degeneration, the
growth of new blood vessels are also associated with tumor
formation in the eye, which results from two mechanisms: the
stimulated growth of endothelial cells of existing blood vessels
through angiogenesis; and a newly discovered vasculature resulting
from highly malignant uveal melanomas, which develop in the eye,
are full of networks of blood channels made by the melanoma cells
themselves (Maniotis et al., American Journal of Pathology 155(3):
739-52 (1999)). It may be that anti-angiogenic agents are
ineffective in the treatment of such neovasculature arising not
from endothelial cells, but from tumor cells such as those of
malignant uveal melanomas.
[0009] Furthermore, because current PDT methods involve the
systemic administration of untargeted photosensitive compounds or
photosensitizers, the required dosages are relatively high which
can lead to skin photosensitivity. The accumulation of
photosensitizers in the skin is a property of all systemically
administered sensitizers in clinical use. For example, clinically
useful porphyrins such as Photophrin.RTM. (QLT, Ltd. brand of
sodium porfimer) are associated with photosensitivity lasting up to
6 weeks. Purlytin.RTM., which is a purpurin, and Foscan.RTM., a
chlorin, sensitize the skin for several weeks. Indeed, efforts have
been made to develop photoprotectants to reduce skin
photosensitivity (see: Dillon et al., Photochemistry and
Photobiology, 48(2): 235-238, 1988; and Sigdestad et al., British J
of Cancer, 74:S89-S92, 1996). In fact, PDT protocols involving
systemic administration of photosensitizer require that the patient
avoid sunlight and bright indoor light to reduce the chance of skin
phototoxic reactions.
[0010] While there are reports in the scientific literature
describing the use of ligand-receptor binding pairs, that
literature is primarily drawn to the treatment of malignant tumor
cells. There are a few reports that address the treatment of
eye-related neovascular diseases such as diabetic retinopathy and
AMD. However, either these reports fail to disclose the use of PDT
at all or these reports fail to teach the use of such methods in
conjunction with the targeting of blood vessels (see, for example:
Savitsky et al., SPIE, 3191: 343-353, 1997; Ruebner et al., SPIE,
2625: 328-332, 1996; Reno et al., U.S. Pat. No. 5,630,996; Casalini
et al., J Nuclear Med., 38(9): 1378-1381, 1997; Griffiths, U.S.
Pat. No. 5,482,698; and Mew et al., J of lmmunol., 130(3):
1473-1477, 1983). It should be noted that even though Strong et al.
U.S. Patent Nos. 5,756,541 and 5,910,510 suggest that a photoactive
agent may be coupled to a specific binding ligand which may bind to
a specific surface component of the target ocular tissue, there is
little guidance provided to suggest appropriate ligands effective
in such PDT methods.
[0011] Regarding light sources for PDT, high powered lasers are
usually employed in order to shorten the procedure time (see:
Strong et al., U.S. Patent Nos. 5,756,541and 5,910,510; and Mori et
al., U.S. Patent No. 5,6333,275; see more generally, W. G. Fisher,
et al., Photochemistry and Photobiology, 66(2):141-155, 1997).
[0012] However, the present art lacks an effective method of
treating neovasculature diseases of the eye using a PDT
methodology, which reduces damage to collateral or healthy tissue
and which does not expose the tissue of the eye to intense laser
light. The present art further teaches the need for recurrent
treatment, the need for which is thought to arise, as discussed
above, due to upregulation of angiogenic factors and/or receptors
secondary to the relative ischemia caused by the PDT treatment as
outlined in the prior art. Clearly there is a need for a therapy
which reduces the number of treatments which probably need to be
performed for the rest of the patient's life.
[0013] Citation of the above documents is not intended as an
admission that any of the foregoing is pertinent prior art. All
statements as to the date or representation as to the contents of
these documents is based on the information available to the
applicants and does not constitute any admission as to the
correctness of the dates or contents of these documents. Further,
all documents referred to throughout this application are
incorporated in their entirety by reference herein.
SUMMARY OF THE INVENTION
[0014] The present invention describes methods to treat neovascular
disease of the eye based on the precise targeting of photosensitive
compounds to target tissue and the activation of these targeted
photosensitizer compounds by subsequently administering to the
subject non-coherent (non-laser) or coherent (laser) light of a
relatively low fluence rate over a prolonged period of time.
[0015] The present invention further discloses the selective
binding of the photosensitizing agent to specific receptors and/or
antigens present on abnormal endothelium or to specific ligands
and/or antibodies which are themselves bindable to endothelial
receptors and antigens. This targeting scheme decreases the amount
of sensitizing drug required for effective therapy, which in turn
reduces the fluence rate or light irradiation needed for effective
photoactivation. As a result, the disclosed method achieves maximal
dosage to abnormal endothelium with minimal side effects or
collateral tissue damage.
[0016] Additionally, the present disclosure teaches the unexpected
use of a low power non-coherent light source utilized for longer
than about 4 minutes. This teaches away from the use of a high
powered, brief exposure using laser light, results in fuller, more
efficient activation of the bound photosensitizers, and enables a
high therapeutic index using a low dose drug. Moreover, a low power
non-coherent light source is relatively inexpensive and simpler to
use. Finally, because the present invention teaches photoactivation
with a non-coherent, broadband light source, different types of
photosensitizers can be activated with a single light source.
[0017] Due to the highly specific nature of the photosensitizer
uptake, excess light or light falling on nonpathologic areas causes
no unwanted photoactivation. Therefore, a region of the retina or
macular with diffuse abnormalities can be safely treated without
damaging intervening normal eye structures. In addition, eye
movement by the patient during treatment, which can result in the
further exposure to light of normal eye structures, is harmless.
Thus, the use of highly targeted photosensitizers allows the
delivery of light in a diffuse fashion and over a prolonged
illumination period. In fact, one embodiment of the invention is
the use of ambient light to activate the photosensitized
neovascular tissue.
[0018] Further, the binding of the photosensitizer/ligand conjugate
to the endothelial receptor, as taught by the present invention,
causes blockage and/or down regulation of the receptor which
further inhibits neovessel formation and subsequent regrowth of
neovasculature, which generally results from more traditional
methods of PDT. Similarly, the use of a photosensitizer/receptor
conjugate would serve to bind circulating ligands also inhibiting
neovessel formation. This added benefit of the present invention
operates independently of the light-activated vessel occlusion
described above.
[0019] An embodiment of the present invention is drawn to a method
for photodynamic therapy ("PDT") of neovascular disease of the eye
comprising: administering to the subject a therapeutically
effective amount of a photosensitizing compound, where the
photosensitizing compound selectively binds to the target abnormal
endothelium that lines or composes the neovasculature target
tissue. This step is followed by illuminating the neovasculature
tissue with light at a wavelength or waveband absorbed by the
targeted photosensitizing compound where the light is provided by a
non-laser light source, and for a period of time sufficient to
activate the photosensitizing compound thereby causing damage to
the neovasculature target tissue. In this embodiment of the present
invention, the targeted photosensitizing compound is cleared from
non-target tissues of the subject prior to irradiation.
[0020] A preferred embodiment of the present invention is drawn to
a method for PDT of neovascular disease of the eye as described
above, wherein the neovascular target tissue is present in the
retina, choroid or both of a subject diagnosed with diabetic
retinopathy or age-related macular degeneration ("AMD"). A further
preferred embodiment of this invention provides a method for PDT of
neovascular tissue associated with tumor formation in the eye, and
more specifically neovascular tissue resulting from angiogenesis or
growth factors elicited by tumors, such as malignant uveal
melanomas.
[0021] A more preferred embodiment of the present invention is
drawn to a method of PDT of neovascular disease of the eye as
described above, wherein the targeted photosensitizing compound is
bound to a first component of a bindable pair and wherein the
second component of the bindable pair is selected from the group
consisting of: receptor present on abnormal endothelium; ligand
bindable to receptor present on abnormal endothelium; antigen
present on abnormal endothelium; and antibody bindable to antigen
present on abnormal endothelium.
[0022] Yet another preferred embodiment contemplates a method of
PDT of neovascular disease of the eye as described above, where the
ligand is selected from the group consisting of: VEGF; VEGF
receptor; and .alpha.-3, .beta.-3 integrin receptor. A further
preferred embodiment provides a method of PDT of neovascular
disease of the eye, where the ligand comprises an antibody specific
or having a high degree of affinity for the extra-domain B (or
ED-B) of fibronectin. An even more preferred embodiment is drawn to
the ligand discussed above, which is a complete or functional
bindable fragment of a human antibody, such as L19 or its
equivalent (see: Birchler et al., Selective targeting and
photocoagulation of ocular angiogenesis mediated by a phage-derived
human antibody fragment, Nature Biotech. 17: 984(1999)).
[0023] Another preferred embodiment of the present invention is
drawn to a method of PDT of neovascular disease of the eye as
described above, where the targeted photosensitizing compound is
bound to a receptor composition that mimics a receptor present on
abnormal endothelium.
[0024] Another preferred embodiment of the present invention is
drawn to a method of PDT of neovascular disease of the eye as
described above, where the targeted photosensitizing compound is
bound to a bi-specific antibody construct that further comprises
both a ligand component and a receptor component.
[0025] A still further embodiment of the present invention is drawn
to a method of PDT of neovascular disease of the eye as described
above, where the targeted and bound photosensitizing compound is
incorporated into a liposomal preparation.
[0026] The invention also provides kits comprising any of the
components that are used in PDT of neovascular disease as taught
herein and instructions (such as an instruction sheet or computer
disk) that teach the methods described herein.
[0027] The invention also provides methods of teaching a person to
conduct treatments of neovascular disease, where the methods
comprise instructing a person to conduct the PDT methods described
herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 illustrates three types of bound photosensitizing
compounds: ligand construct, receptor construct, and bispecific
antibody construct.
[0029] FIG. 2 illustrates a photosensitizing compound incorporated
into a liposomal preparation that includes a ligand construct,
receptor construct, and bispecific antibody construct.
[0030] FIG. 3 shows an eye subjected to ambient light and
collimated LED light.
[0031] FIG. 4 shows a lateral view of skull (partial) with
placement of LED light sources.
DETAILED DESCRIPTION OF THE INVENTION
[0032] This invention provides methods for treating neovascular
disease of the eye by the specific and selective binding of a
photosensitizing compound to the abnormal endothelium that lines or
composes the neovasculature target tissue. This method comprises
illuminating the photosensitized target tissue with light for a
period of time sufficient to activate the bound photosensitizing
compound thereby causing damage to the neovasculature target
tissue.
[0033] Specifically, the present invention is based on the precise
targeting of photosensitizing compounds to specific target
receptors and/or antigens present on abnormal endothelium or to
specific ligands and/or antibodies which are themselves bindable to
endothelial receptors and antigens, and to the method of activation
of the bound and targeted photosensitizing compounds by
subsequently administering to the target tissue light of a
relatively low fluence rate over a prolonged period of time. The
disclosed method achieves maximal damage to abnormal endothelium
with minimal side effects or collateral tissue damage.
[0034] Terms as used herein are based upon their art recognized
meaning and from the present disclosure should be clearly
understood by the ordinary skilled artisan. For sake of clarity,
terms may also have particular meaning as would be clear from their
use in context.
[0035] Further, as used herein, "target tissues" are those tissues
that are intended to be impaired or destroyed by this treatment
method. Photosensitizing compounds bind to these target tissues;
then when sufficient radiation is applied, these tissues are
impaired or destroyed.
[0036] "Non-target tissues" are all the tissues of the eye which
are not intended to be impaired or destroyed by the treatment
method. These non-target tissues include but are not limited to
healthy blood cells, and other normal tissue of the retina and
choroid, not otherwise identified to be targeted.
[0037] "Photosensitizing compound" is a chemical compound which
homes to one or more types of selected target cells and, when
contacted by radiation, absorbs the light, which results in
impairment or destruction of the target cells. Virtually any
chemical compound that homes to a selected target and absorbs light
may be used in this invention. Preferably, the chemical compound is
nontoxic to the subject to which it is administered or is capable
of being formulated in a nontoxic composition. Preferably, the
chemical compound in its photodegraded form is also nontoxic. A
comprehensive listing of photosensitive chemicals may be found in
Kreimer-Bimbaum, Sem. Hematol. 26:157-73, 1989. Photosensitive
compounds include, but are not limited to, chlorins,
bacteriochlorophylls, phthalocyanines, porphyrins, purpurins,
merocyanines, psoralens, benzoporphyrin derivatives (BPD) and
porfimer sodium and pro-drugs such as .delta.-aminolevulinic acid,
which can produce drugs such as protoporphyrin. Other compounds
include indocyanine green (ICG); methylene blue; toluidine blue;
texaphyrins; and any other agent that absorbs light in a range of
500 nm -1100 nm.
[0038] "Illumination" as used herein includes all wave lengths and
wavebands. Preferably, the illumination wave length or waveband is
selected to match the wave length(s) or wavebands which excite the
photosensitive compound. Even more preferably, the radiation wave
length or waveband matches the excitation wave length or waveband
of the photosensitive compound and has low absorption by the
non-target tissues of the eye, and the rest of the subject,
including blood proteins.
[0039] The irradiation by illumination is further defined in this
invention by its coherence (laser) or non-coherence (non-laser), as
well as intensity, duration, and timing with respect to dosing
using the photosensitizing compound. The intensity or fluence rate
must be sufficient for the light to reach the target tissue. The
duration or total fluence dose must be sufficient to photoactivate
enough photosensitizing compound to act on the neovasculature
target tissue. Both intensity and duration must be limited to avoid
overtreating the subject. Timing with respect to dosing with the
photosensitizing compound is important, because 1) the administered
photosensitizing compound requires some time to home in on
neovasculature target tissue and 2) the blood level of many
photosensitizing compounds decreases with time.
[0040] Briefly, the photosensitizing compound is generally
administered to the subject before the neovasculature target tissue
is subjected to illumination.
[0041] Preferred photosensitizing compounds include, but are not
limited to, chlorins, bacteriochlorophylls, phthalocyanines,
porphyrins, purpurins, merocyanines, psoralens and pro-drugs such
as .delta.-aminolevulinic acid, which can produce drugs such as
protoporphyrin. More preferred are: methylene blue; toluidine blue;
texaphyrins; and any other agent that absorbs light in a range of
600 nm -1100 nm. Most preferred is indocyanine green (for example,
see: WO 92/00106 (Raven et al.); WO97/31582 (Abels et al.) and
Devoisselle et al., SPIE 2627:100-108, 1995). Additional
photosensitizing compounds, include: pyropheophorbide compounds
(see: U.S. Patent No.: 5,459,159); bacteriochlorophyll derivatives
(see: U.S. Patent No.: 5,955,585); and Alkyl ether analogs of
chlorins (see: U.S. Patent No.: 5,952,366).
[0042] Any one or combination of these or other photosensitizing
compounds may be supplied in a kit of this invention along with
instructions on conducting any of the methods disclosed herein.
Instructions may be in any tangible form, such as printed paper, a
computer disk that instructs a person how to conduct the method, a
video cassette containing instructions on how to conduct the
method, or computer memory that receives data from a remote
location and illustrates or otherwise provides the instructions to
a person (such as over the Internet). A person may be instructed in
how to use the kit using any of the instructions above or by
receiving instructions in a classroom or in the course of treating
a patient using any of the methods disclosed herein, for
example.
[0043] The photosensitizing compound is administered orally,
intravenously by injection, or via the intraocular route. The
photosensitizing compound can be conjugated to various antibodies,
antibody fragments, and other molecules and compounds capable of
binding to the endothelium of neovessels. The specific ligands
reactive with the target endothelium include antibodies and
antibody fragments that bind to abnormal or upregulated vascular
endothelial receptors such as the VEGF receptors and .alpha.-3,
.beta.-3 integrins (see: Ferrara, Curr Top Microbiol Immunol,
237:1-30, 1999; Elicieri and Cheresh, The Journal of Clinical
Investigation, 103:1227-30, 1999; Smith et al., Br J Opthamol,
83:486-494, 1999). Also, the antibody can be drawn to and have
affinity to bind to the extra-domain B (or ED-B) of fibronectin.
Such antibodies, include a complete or functional bindable fragment
of a human antibody, such as L19 or its equivalent (see: Birchler
et al., Selective targeting and photocoagulation of ocular
angiogenesis mediated by a phage-derived human antibody fragment,
Nature Biotech. 17: 984 (1999)). The ligand can be any molecule or
compound that binds to a endothelial receptor found on an abnormal
blood vessel wall. Preferably the ligand binds selectively to
receptors which are mainly or only found on the abnormal blood
vessel wall.
[0044] Another embodiment of the present invention involves the use
of a photosensitizing compound bound to a receptor-type molecule or
compound. The receptor mimics the type of receptors found on the
endothelium of abnormal vessel walls. Preferably the receptor mimic
binds ligands, such VEGF, that are found to be elevated in
concentration or are not normally present due to the abnormal
conditions relating to the abnormal blood vessel formation. An
additional embodiment involves the use of a bispecific antibody
construct that is a combination ligand and receptor type molecule
or compound that is bound to a photosensitizing compound. The
bispecific nature of this construct allows binding of either an
abnormal endothelial receptor or an abnormal ligand or abnormally
elevated concentration of ligand.
[0045] Alternatively, the photosensitizing compound can be packaged
into liposomes and the ligand, receptor, or bispecific construct
incorporated or attached to the liposome to serve as a further
means of targeting. In each of the above embodiments, preferably
more than one photosensitizing compound is attached to the
targeting moiety.
[0046] The technique of constructing bispecific antibodies, the
techniques and methods of linking photosensitizers to targeting
agents, and the techniques of producing targeted liposomes are well
known in the art. For example, useful reviews of such techniques
are provided by Yatvin et al., U.S. Patent No. 5,827,819 (1998) and
Jansen, et al., U.S. Patent No. 5,869,457 (1999).
[0047] The bound photosensitizing compound can be administered in a
dry formulation, such as pills, capsules, suppositories or patches.
The compound also may be administered in a liquid formulation,
either alone with water, or with pharmaceutically acceptable
excipients, such as are disclosed in Remington's Pharmaceutical
Sciences. The liquid formulation also can be a suspension or an
emulsion. In particular, liposomal or lipophilic formulations are
desirable. If suspensions or emulsions are utilized, suitable
excipients include water, saline, dextrose, glycerol, and the like.
These compositions may contain minor amounts of nontoxic auxiliary
substances such as wetting or emulsifying agents, antioxidants, pH
buffering agents, and the like.
[0048] The dose of photosensitizing compound can be determined
clinically and will be the lowest dose that saturates the available
binding sites. Depending on the photosensitizing compound used, an
equivalent optimal therapeutic level will have to be established. A
certain length of time is allowed to pass for the circulating or
locally delivered photosensitizer to be taken up by the endothelium
of the neovessels. The unbound photosensitizer is cleared from the
circulation during this waiting period. The waiting period will be
determined clinically and may vary from compound to compound.
[0049] At the conclusion of this waiting period, a non-laser light
source is used to activate the bound drug, although a laser light
source may be used. The spot size illuminating the retina or
choroid is determined by the location and dimension of the
pathologic region to be treated. The duration of illumination
period will be determined empirically, but is preferably a total or
cumulative period of time between about 4 minutes and 72 hours.
More preferably, the illumination period is between about 60
minutes and 148 hours. Most preferably, the illumination period is
between about 2 hrs and 24 hours.
[0050] Preferably, the total fluence or energy of the light used
for irradiating, as measured in Joules, is between about 30 Joules
and about 25,000 Joules; more preferably, between about 100 Joules
and about 20,000 Joules; and most preferably, between about 500
Joules and about 10,000 Joules. Light having a waveband
corresponding at least in part with the characteristic light
absorption waveband of said photosensitizing agent is used for
irradiating the target tissue.
[0051] The intensity or power of the light used is measured in
watts, with each Joule equal to one watt-sec. Therefore, the
intensity of the light used for irradiating in the present
invention may be substantially less than 500mW/cm.sup.2. Since the
total fluence or amount of energy of the light in Joules is divided
by the duration of total exposure time in seconds, the longer the
amount of time the target is exposed to the irradiation, the
greater the amount of total energy or fluence may be used without
increasing the amount of the intensity of the light used. The
present invention employs an amount of total fluence of irradiation
that is sufficiently high to activate the photosensitizing agent,
as applicable, with a concomitant reduction in the intensity of
light and collateral or non-target specific tissue damage.
[0052] While not wishing to be limited by a theory, the inventor
proposes that a targeted photosensitizing compound can be
substantially and selectively photoactivated in the neovasculature
target tissue within a therapeutically reasonable period of time
and without excess toxicity or collateral damage to non-target
tissues. A relatively low fluence can be used for a relatively long
period of time in order to fully photoactivate the drug in order to
insure adequate closure of the neovessels and vessel
abnormalities.
[0053] Having now generally described the invention, the same will
be more readily understood through reference to the following
examples which are provided by way of illustration, and are not
intended to be limiting of the present invention, unless
specified.
EXAMPLES
EXAMPLE 1
Treatment of Choroidal Neovasculature Lesions
[0054] A subject with choroidal neovascularization (CNV) from
age-related macular generation is assessed using standard visual
acuity testing, ophthalmic examination, color photographs and
fluorescein angiograms (see Miller et al., Ach. Ophthal. vol.
117:1161-1173(1999)).
[0055] A photosensitizing agent, verteporfin, is conjugated using
generally recognized methods in the art to a bindable fragment of
the L19 antibody demonstrating high affinity to the ED-B of
fibronectin (Birchler et al., Nature Biotech. 17: 984 (1999)). A
therapeutically effective amount of the photosensitizing agent
conjugate, approximately 5 mg/m.sup.2, is administered
intravenously to the subject.
[0056] Following a period of approximately 1 hour, to permit the
non-specifically bound photosensitizing agent conjugate to clear
from collateral tissues, the subject is irradiated in one or more
sessions for a total period of 10 minutes with 400 mW/cm.sup.2 of
collimated LED light having a wavelength of 690 nm. This represents
a total fluence of 240 Joules/cm.sup.2.
[0057] The entire lesion is treated with a single spot of the size
as determined from a pretreatment angiogram. A margin of 300-500
.mu.m may be added to ensure complete coverage of the lesion. A
green non-activating observation light beam may be used for
real-time observation and aiming during PDT.
[0058] Screening examinations may be performed during the first
week immediately before treatment. Visual acuity is measured by
standard refraction protocol using EDTRS criteria. A slit-lamp and
a complete ophthalmoscopic exam is performed. Optic discs and
maculae of both eyes are documented by stereo color photography.
Stereo fluorescein angiography is performed with 10% sodium
fluorescein. Frames are taken according to MPS standards. The
photodynamic effects are monitored after 1, 4, and 12 weeks by
means of visual acuity, ophthalmoscopy, fundus photography and
stereo angiography. Angiograms are evaluated for angiographic
occlusion and leakage after PDT.
EXAMPLE 2
Treatment of Retinal Neovasculature Lesions
[0059] According to Example 1, a liposomal benzoporphyrin
derivative is conjugated to VEGF for use as a photosensitizer. A
drug dose of 10 mg/m.sup.2 is administered to a subject with
neovascular lesions in the retina of the eye via intravenous
infusion over 10 minutes. The subject waits for a period of 6 hours
to permit clearance from the tissues of non-specifically bound
photosensitizing conjugate before illumination therapy is
administered.
[0060] With the photosensitizer specifically localized to the
retinal neovasculature lesions comprising VEGF receptor on the
surface of the cells of the lesion, the subject is exposed to
non-coherent light from a low power non-coherent broadband light
source emitting at 690 nm. This illumination provides a radiant
exposure of no more than 500 mW/cm.sup.2 for a period of
approximately 20 minutes in one or more sessions producing a total
fluence of illumination of about 600 Joules/cm.sup.2.
Alternatively, coherent or laser light could be similarly employed.
Photosensitization is performed with dilated pupils and topical
anesthesia using a contact lens.
[0061] The entire lesion is treated with a single spot of the size
as determined from a pretreatment angiogram. A margin of 300-500
.mu.m is added to ensure complete coverage of the lesion. A green
non-activating observation light beam is used for real-time
observation and aiming during PDT. Screening examinations and
visual acuity as disclosed in Example 1 is performed.
EXAMPLE 3
Treatment of Vascular Tumors of the Eye
[0062] Integrin .alpha..nu..beta.3 integrin is expressed by
vascular cells during angiogenesis and vascular remodeling and is
highly expressed by endothelial cells undergoing angiogenesis in
tumors. See Eliceiri, B. P. et al., J. Clin. Invest (1999)
103(9):1227-1230. Antibody elicited to .alpha..nu..beta.3, such as
LM609 (Vitaxin; Eliceiri et al.) is conjugated to a texaphyrin
photosensitizing agent in a liposomal formulation. A drug dose of
25 mg/m.sup.2 is administered via intravenous infusion over 10 min.
The photosensitizer localizes to the neovasculature lesions. The
pupils are dilated to allow ambient light enter for
photosensitization. Therefore, no slit lamp is needed for
photosensitization and the subject may continue everyday activities
while receiving PDT. The ambient light is used to photoactivate the
photosensitizing agent for a total exposure time of 24 hours.
[0063] Screening examinations and visual acuity as disclosed in
Example 1 is performed.
EXAMPLE 4
Treatment Choroidal Tumor of the Eye
[0064] Most ocular tumors metastasize from systemic origins in
breast carcinoma in females, and bronchial carcinoma in males (Chen
Y. R., et al., Bilateral choroidal metastases as the initial
presentation of a small breast carcinoma: a case report, Chung Hua
I Hsueh Tsa Chih (Taipei); 61(2):99-103 1998). Antibody elicited to
carcinoembryonic antigen (CEA), which is associated with the
choroidal tumor, is conjugated to a benzoporphyrin derivative
photosensitizing agent in a liposomal formulation. A drug dose of
10 mg/m.sup.2 is administered via intravenous infusion over 10
min.
[0065] Additionally, the patient is administered the
anti-.alpha..nu..beta.3 antibody-texaphyrin conjugate at a drug
dose of 25 mg/M.sup.2 as provided in Example 3.
[0066] After the texaphyrin photosensitizer conjugate localizes to
the neovasculature lesion and the benzoporphyrin-anti-CEA conjugate
localizes to the CEA tumor antigens, a period of 6 hours is
permitted to pass to permit the unbound or nonspecifically bound
photosensitizer conjugates to clear from the lesions.
[0067] A low power non-coherent broadband light source emitting at
690 nm is used as described in Example 2. The radiant exposure of
250 mW/cm.sup.2 is employed for approximately 1 hour over the
course of one or more sessions to provide a total fluence of 900
J/cm.sup.2. Photosensitization is performed with dilated pupils and
topical anesthesia using a contact lens. The entire lesion is
treated with a single spot of the size as determined from a
pretreatment angiogram. A margin of 300-500 .mu.m is added to
ensure complete coverage of the lesion. A green non-activating
observation light beam is used for real-time observation and aiming
during PDT. Screening examinations and visual acuity as disclosed
in Example 1 is performed.
[0068] Although the present invention has been described in
connection with the preferred form of practicing it, those of
ordinary skill in the art will understand that many modifications
can be made thereto within the scope of the claims that follow.
Accordingly, it is not intended that the scope of the invention in
any way be limited by the above description, but instead be
determined entirely by reference to the claims that follow.
* * * * *