Non-invasive delivery method of antibodies to the brain for treatment of brain diseases

Abstract

Disclosed herein are methods for delivering an antibody or antigen binding fragment thereof to a brain of a subject, comprising: administering the antibody or antigen binding fragment thereof to an eye of the subject.

Description

Docket No. 11605-057W01NON-INVASIVE DELIVERY METHOD OF ANTIBODIES TO THE BRAIN FOR TREATMENT OF BRAIN DISEASESCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 535,586, filed August 31, 2023, which is incorporated by reference herein in its entirety.SUMMARY

[0002] In an aspect, provided is a method for delivering an antibody or antigen binding fragment thereof to a brain of a subject, comprising: administering the antibody or antigen binding fragment thereof to an eye of the subject.

[0003] In some aspects, the antibody or antigen binding fragment thereof is administered to the subject using an eye dropper device.

[0004] In some aspects, the antibody or antigen binding fragment thereof is a hG-CSF antibody. In some aspects, the antibody or antigen binding fragment thereof is lecanemab. In some aspects, the antibody or antigen binding fragment thereof is a monoclonal antibody. In some aspects, the antibody or antigen binding fragment thereof is a polyclonal antibody. In some aspects, the antibody or antigen binding fragment thereof is a human antibody. In some aspects, the antibody or antigen binding fragment thereof is a humanized antibody. In some aspects, the antibody or antigen binding fragment thereof is a chimeric antibody.

[0005] In some aspects, the method further comprises the step of detecting the antibody or antigen binding fragment thereof in the brain of the subject.

[0006] In another aspect, provided is a method of treating a brain disease or disorder in a subject, comprising: administering an antibody or antigen binding fragment thereof to an eye of the subject.

[0007] In some aspects, the antibody or antigen binding fragment thereof is administered to the subject using an eye dropper device.

[0008] In some aspects, the antibody or antigen binding fragment thereof is a hG-CSF antibody. In some aspects, the antibody or antigen binding fragment thereof is lecanemab. In some aspects, the antibody or antigen binding fragment thereof is a monoclonal antibody. In some aspects, the antibody or antigen binding fragment thereof is a polyclonal antibody. In some aspects, the antibody or antigen binding fragment thereof is a human antibody. In someDocket No. 11605-057W01 aspects, the antibody or antigen binding fragment thereof is a humanized antibody. In some aspects, the antibody or antigen binding fragment thereof is a chimeric antibody.

[0009] In some aspects, the brain disease or disorder is selected from Alzheimer’s Disease, Parkinson’s Disease, or a brain cancer. In some aspects, the brain disease or disorder is Alzheimer’s Disease.

[0010] Other systems, methods, features and / or advantages will be or may become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features and / or advantages be included within this description and be protected by the accompanying claims.BRIEF DESCRIPTION OF DRAWINGS

[0011] FIGS. 1A-1D depict that in areas associated with visual pathways, fluorescence activity is markedly upregulated in antibody treated mice. Representative images (40x, confocal) of polyclonal antibody (green) and Dapi (blue) observed in the visual pathway to CNS are shown. Scale bar, 10 pm. Results of quantitative analysis of images of antibody expression in the brain regions including the Optic tract, the Optic chiasm, Dorsal lateral geniculate nucleus and Primary visual cortex are shown on the right panel. FIGS. 1A-1D show antibody expression by the representative section of wild type (WT), wild type mice that were treated with polyclonal antibody (WT + pAb), transgenic AD mice, (App23), and AD mice that were treated with polyclonal antibody (App23 + pAb) in the Optic tract along the visual pathway (FIG. 1A), in the Optic chiasm (FIG. IB), Dorsal lateral geniculate nucleus (FIG. 1C), and primary visual cortex (FIG. ID). In addition, antibody expression in the Optic tract (OT) of the App23 mice treated with polyclonal antibody and the Optic chiasm (Och) of the C57BL6 / J mice treated with polyclonal antibody are shown in FIG. IE and FIG. IF, respectively.

[0012] FIGS. 2A-2D depict those in areas associated with visual processing, fluorescence activity is also markedly upregulated in antibody treated mice. Representative images (40x, confocal) of polyclonal antibody (green) and Dapi (blue) observed in CNS are shown. Scale bar, 10 pm. Results of quantitative analysis of images of antibody expression in the brain regions including the Superior colliculus, the Hippocampal (CA3), secondary visual cortex and Nucleus of the optic tract (OT) are shown on the right panel. FIGS. 2A-2D show antibody expression by the representative section of wild type (WT), wild type mice that were treated with polyclonal antibody (WT + pAb), transgenic AD mice (App23), and AD mice that were treated with polyclonal antibody (App23+pAb) in the superior colliculus that plays anDocket No. 11605-057W01 important role in the visual reflexes (FIG. 2A), in the hippocampal (CA3) which is involved in visual processing and memory formation of visual stimuli (FIG. 2B), secondary visual cortex (FIG. 2C), and nucleus of the optic tract (OT) (FIG. 2D). In addition, antibody expression in the Hippocampal region of the C57BL6 / J mice treated with or without polyclonal antibody (pAb) (marked as C57BL6 / J + pAb and C57BL6 / J, respectively) are shown in FIG. 2E.

[0013] FIGS. 3A-3C depict that fluorescence activity is also markedly upregulated in antibody treated mice in areas that are involved in visual processing of motor stimuli. Representative images (40x, confocal) of polyclonal antibody (green) and Dapi (blue) observed in the visual pathway to CNS are shown. Scale bar, 10 pm. FIGS. 3A-3C show antibody expression by the representative section of wild type (WT), wild type mice that were treated with polyclonal antibody (WT + pAb), transgenic AD mice (App23), and AD mice that were treated with polyclonal antibody (App23 + pAb) in the red nucleus (FIG. 3A), in the Substantial nigra (FIG. 3B), and pontine nucleus (FIG. 3C). Results of quantitative analysis of images of antibody expression in the brain regions including the Red nucleus, the Substantial nigra (SN) and Pontine nucleus are shown on the right panel. In addition, antibody expression in the Substantial nigra of the C57BL6 / J mice treated with or without polyclonal antibody (marked as C57BL6 / J + pAb and C57BL6 / 7, respectively) are shown in FIG. 3D. Similarly, antibody expression in the Red nucleus of the C57BL6 / J mice treated with polyclonal antibody (marked as C57 + pAb) and in the Pontine nucleus of both the C57BL6 / J mice and App23 mice treated with polyclonal antibody (marked as C57+ pAb and App23 + pAb, respectively) are shown in FIG. 3E and FIG. 3F, respectively.

[0014] FIG. 4 shows a confocal image of Hippocampal area in transgenic mice, App23, that were administered with polyclonal antibody (marked as App23 + pAb). The square indicated in the upper panel is enlarged and showed the staining of delivered antibody as bright green fluorescence (Right picture, Lower panel), DAPI staining of nucleus as blue fluorescence (Middle picture, Lower panel), A merged picture (Left picture, Lower panel) showing a colocalization of delivered antibody with DAPI, a marker of neural cell.

[0015] FIG. 5 shows a confocal image of Hippocampal area in C57BL6 / J mice that were administered with polyclonal antibody(marked as C57BL6 / J + pAb). The square indicated in the upper panel is enlarged and showed the staining of delivered antibody as bright green fluorescence (Middle picture, Lower panel), DAPI staining of nucleus as blue fluorescence (Left picture, Lower panel), A merged picture (Right picture, Lower panel) showing a colocalization of delivered antibody with DAPI, a marker of neural cell.Docket No. 11605-057W01DETAILED DESCRIPTION

[0016] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate aspects, can also be provided in combination with a single aspect. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single aspect, can also be provided separately or in any suitable subcombination. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure.DEFINITIONS

[0017] In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings:

[0018] Throughout the description and claims of this specification, the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and are not intended to exclude, for example, other additives, segments, integers, or steps. Furthermore, it is to be understood that the terms comprise, comprising, and comprises as they relate to various aspects, elements, and features of the disclosed invention also include the more limited aspects of “consisting essentially of’ and “consisting of.”

[0019] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a “polymer” includes aspects having two or more such polymers unless the context clearly indicates otherwise.

[0020] Ranges can be expressed herein as from “about” one particular value and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It should be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0021] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.Docket No. 11605-057W01

[0022] For the terms "for example" and "such as," and grammatical equivalences thereof, the phrase "and without limitation" is understood to follow unless explicitly stated otherwise.

[0023] The term “antibodies” is used herein in a broad sense and includes both polyclonal and monoclonal antibodies. In addition to intact immunoglobulin molecules, also included in the term “antibodies” are fragments or polymers of those immunoglobulin molecules, and human or humanized versions of immunoglobulin molecules or fragments thereof. The antibodies can be tested for their desired activity using the in vitro assays described herein, or by analogous methods, after which their in vivo therapeutic and / or prophylactic activities are tested according to known clinical testing methods. There are five major classes of human immunoglobulins: IgA, IgD, IgE, IgG and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG-1, IgG-2, IgG-3, and IgG-4; IgA-1 and IgA-2. One skilled in the art would recognize the comparable classes for mouse. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively.

[0024] The term “monoclonal antibody” as used herein refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies within the population are identical except for possible naturally occurring mutations that may be present in a small subset of the antibody molecules. The monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, as long as they exhibit the desired antagonistic activity.

[0025] As used herein, the term “antibody or antigen binding fragment thereof’ or “antibody or fragments thereof’ encompasses chimeric antibodies and hybrid antibodies, with dual or multiple antigen or epitope specificities, and fragments, such as F(ab’)2, Fab’, Fab, Fv, sFv, scFv and the like, including hybrid fragments. Thus, fragments of the antibodies that retain the ability to bind their specific antigens are provided. Such antibodies and fragments can be made by techniques known in the art and can be screened for specificity and activity according to the methods set forth in the Examples and in general methods for producing antibodies and screening antibodies for specificity and activity (See Harlow and Lane. Antibodies, A Laboratory Manual. Cold Spring Harbor Publications, New York, (1988)).Docket No. 11605-057W01

[0026] Also included within the meaning of “antibody or antigen binding fragment thereof’ are conjugates of antibody fragments and antigen binding proteins (single chain antibodies). Also included within the meaning of “antibody or antigen binding fragment thereof’ are immunoglobulin single variable domains, such as for example a nanobody.

[0027] The fragments, whether attached to other sequences or not, can also include insertions, deletions, substitutions, or other selected modifications of particular regions or specific amino acids residues, provided the activity of the antibody or antibody fragment is not significantly altered or impaired compared to the non-modified antibody or antibody fragment. These modifications can provide for some additional property, such as to remove / add amino acids capable of disulfide bonding, to increase its bio-longevity, to alter its secretory characteristics, etc. In any case, the antibody or antibody fragment must possess a bioactive property, such as specific binding to its cognate antigen. Functional or active regions of the antibody or antibody fragment may be identified by mutagenesis of a specific region of the protein, followed by expression and testing of the expressed polypeptide. Such methods are readily apparent to a skilled practitioner in the art and can include site- specific mutagenesis of the nucleic acid encoding the antibody or antibody fragment. (Zoller, M.J. Curr. Opin. Biotechnol. 3:348-354, 1992).

[0028] As used herein, the term “antibody” or “antibodies” can also refer to a human antibody and / or a humanized antibody. Many non-human antibodies (e.g., those derived from mice, rats, or rabbits) are naturally antigenic in humans, and thus can give rise to undesirable immune responses when administered to humans. Therefore, the use of human or humanized antibodies in the methods serves to lessen the chance that an antibody administered to a human will evoke an undesirable immune response.

[0029] As used herein, the term “subject” can refer to living organisms such as mammals, including, but not limited to humans, livestock, dogs, cats, and other mammals. Administration of the therapeutic agents can be carried out at dosages and for periods of time effective for treatment of a subject. In some aspects, the subject is a human.

[0030] The terms “treat,” “treating,” “treatment,” and grammatical variations thereof as used herein, include partially or completely delaying, alleviating, mitigating or reducing the intensity of one or more attendant symptoms of a cancer or condition and / or alleviating, mitigating or impeding one or more causes of a cancer. Treatments according to the invention may be applied preventively, prophylactically, palliatively or remedially. Prophylactic treatments are administered to a subject prior to onset (e.g., before obvious signs of disease onset), during early onset (e.g., upon initial signs and symptoms of disease onset), after anDocket No. 11605-057W01 established development of a disease, or during chronic disease. Prophylactic administration can occur for several minutes to months prior to the manifestation of an infection.METHODS

[0031] In an aspect, provided is a method for delivering an antibody or antigen binding fragment thereof to a brain of a subject, comprising: administering the antibody or antigen binding fragment thereof to an eye of the subject.

[0032] In some embodiments, the antibody or antigen binding fragment thereof is administered to the subject intraocularly. In some embodiments, the antibody or antigen binding fragment thereof is administered to the subject using an eye dropper device. In some aspects, the antibody or antigen binding fragment thereof is administered to the subject via intraocular injection. In some aspects, the antibody or antigen binding fragment thereof is administered to the subject using an ocular implant. In some aspects, the antibody or antigen binding fragment thereof is administered to the subject using a therapeutic contact lens. In some aspects, the antibody or antigen binding fragment thereof is administered to the subject systemically either exclusively or in combination with any of the aforementioned intraocular delivery routes. In some aspects, a lower dose of the antibody or antigen binding fragment thereof is used for intraocular administration than systemic administration due to improved delivery through the eye.

[0033] In some aspects, the antibody or antigen binding fragment thereof is a hG-CSF antibody. In some aspects, the antibody or antigen binding fragment thereof is lecanemab. In some aspects, the antibody or antigen binding fragment thereof is a monoclonal antibody. In some aspects, the antibody or antigen binding fragment thereof is a polyclonal antibody. In some aspects, the antibody or antigen binding fragment thereof is a human antibody. In some aspects, the antibody or antigen binding fragment thereof is a humanized antibody. In some aspects, the antibody or antigen binding fragment thereof is a chimeric antibody.

[0034] In some aspects, the method further comprises the step of detecting the antibody or antigen binding fragment thereof in the brain of the subject. In some aspects, the step of detecting the antibody or antigen binding fragment thereof in the brain of the subject.

[0035] In another aspect, provided is a method of treating a brain disease or disorder in a subject, comprising: administering an antibody or antigen binding fragment thereof to an eye of the subject.

[0036] In some aspects, the antibody or antigen binding fragment thereof is administered to the subject intraocularly. In some aspects, the antibody or antigen binding fragment thereofDocket No. 11605-057W01 is administered to the subject using an eye dropper device. In some aspects, the antibody or antigen binding fragment thereof is administered to the subject via intraocular injection. In some aspects, the antibody or antigen binding fragment thereof is administered to the subject using an ocular implant. In some aspects, the antibody or antigen binding fragment thereof is administered to the subject using a therapeutic contact lens. In some aspects, the antibody or antigen binding fragment thereof is administered to the subject systemically either exclusively or in combination with any of the aforementioned intraocular delivery routes.

[0037] In some aspects, a lower dose of the antibody or antigen binding fragment thereof is used for intraocular administration than systemic administration due to improved delivery through the eye. If antibody is delivered through the systemic circulations, less than 0.1% of the antibody reach the brain (Petereit et al.).

[0038] In some aspects, the antibody or antigen binding fragment thereof is a hG-CSF antibody. In some aspects, the antibody or antigen binding fragment thereof is lecanemab. In some aspects, the antibody or antigen binding fragment thereof is a monoclonal antibody. In some aspects, the antibody or antigen binding fragment thereof is a polyclonal antibody. In some aspects, the antibody or antigen binding fragment thereof is a human antibody. In some aspects, the antibody or antigen binding fragment thereof is a humanized antibody. In some aspects, the antibody or antigen binding fragment thereof is a chimeric antibody. In some aspects, antibodies delivered ocularly are transported to the brain through the projection of retinal ganglion cell to the brain through optic tract, optic chiasm, dorsal lateral geniculate nucleus, superior colliculus and primary visual cortex via exocytosis and endocytosis mechanism. In some aspects, other proteins such as brain-derived neurotrophic factor (BDNF) can also be delivered ocularly.

[0039] In some aspects, the brain disease or disorder is selected from adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), aphasia, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, ataxia, ALS and neuromuscular diseases, autism and neurodevelopment, Batten disease, Bell’s palsy, brain and nerve tumors, Cushing’s syndrome, cerebral palsy, chronic traumatic encephalopathy (CTE), concussion, dystonia, dyslexia, dementia - Alzheimer’s and LBD, encephalitis, epilepsy, fibromyalgia, frontotemporal disorders, Guillain-Barre syndrome, headache, Huntington’s disease, Lewy body dementia, mal de debarquement syndrome (MdDS), meningitis, migraine, myasthenia gravis, multiple sclerosis, muscular dystrophy, movement disorders, neurogenetic diseases, neuroinfectious diseases, neurorehabilitation, peripheral neuropathy, Parkinson’s disease, stiff person syndrome, sleep disorders, spinal muscular atrophy, stroke, tremors, TouretteDocket No. 11605-057W01 syndrome, traumatic brain injury, brain cancer, or other brain diseases or disorders. In some aspects, the brain cancer is selected from glioma, astrocytoma, ependymomas, glioblastoma, oligodendroglioma, ganglioglioma, hemangioblastoma, medulloblastoma, meningioma, rhabdoid tumors, schwannoma, pituitary adenoma, craniopharyngioma, nasopharyngeal angiofibroma, choroid plexus tumors, dysembryoplastic neuroepithelial tumors, neurofibroma, or other brain cancers. In some aspects, the brain disease or disorder is selected from Alzheimer’s Disease, Parkinson’s Disease, or a brain cancer. In some aspects, the brain disease or disorder is Alzheimer’s Disease.EXAMPLESExample 1

[0040] One of the difficulties for treating brain diseases using immunotherapy is the presence of blood-brain barrier (BBB) that limits the entrance of antibodies into the brain via non-invasive delivery systems. It is estimated that only 0.1-0.2% of injected dose of antibody in circulation made into the brain (Kouhi et al., 2021). As a result, even if candidate antibodies for the therapy of brain diseases may be already available, they cannot be utilized because of their poor blood-to-brain penetration due to the presence of the tight-junctioned BBB preventing the passage of antibodies (Grabrucker et al., 2016). To circumvent this difficulty, described is a new delivery system of antibodies to the brain by a non-invasive and simple method using eye-drop application. Polyclonal antibody (pAb) against human granulocyte-colony stimulating factor (hG-CSF) produced in rabbit was applied to both normal C57BL6 / J wild type mouse and Alzheimer’s disease transgenic mouse, App23 (APP isoform 751 containing Swedish mutation), by eye-drop application, and it was found that the administered pAb was detected as green fluorescence at high to moderate level in various brain regions including the optic tract, the optic chiasm, dorsal lateral geniculate nucleus and the primary visual cortex (Fig 1). Furthermore, the administered pAb is on or around the neural cells as indicated by DAPI staining (blue color).

[0041] In addition, the administered pAb was also detected at high to moderate level in other brain regions including the superior colliculus, the hippocampal (CA3), secondary visual cortex and nucleus of the optic tract (OT) (Fig. 2), as well as in the red nucleus, the substantial nigra, and the pontine nucleus (Fig.3). Results from quantitative analysis further demonstrated a high level of antibody reached in many brain areas that have been examined. These results demonstrate that antibodies could be delivered by eye-drop application and reach many parts of the brain at high levels.Docket No. 11605-057W01

[0042] Furthermore, the hippocampus has been used as an example to show that the administered pAb indeed was present at high levels in the hippocampus and localized in or around the neural cells as indicated in the localization with DAPI, a marker for cell nucleus, in AD transgenic mice, App23 (Fig. 4) and the wild type mice, C57BL / J (Fig. 2E and Fig. 5)

[0043] Polyclonal antibodies against human granulocyte-colony stimulating factor (hGCSF) were applied to the left eye sac by eye-drop application in a volume of 1.5 ul containing a dose of antibodies of 0.6 ug in saline solution 24 hours before the animals were euthanized. The same dose of antibodies was administered as before by eye-drop application 4 hours before the animals were euthanized. Both C57BL6 / J wild type mouse and Alzheimer’s disease transgenic mouse, App23 (APP isoform 751 containing Swedish mutation), at six - month old were used in the study. The presence of administered antibodies in the mouse brain was then identified by immunofluorescence microscopic examination as described below:

[0044] Immunohistochemistry Procedure: Mice were anesthetized with isoflurane and perfused with 0.9% saline solution followed by 4% paraformaldehyde (PFA) solution. Brain were then extracted and post-fixed in 4% PFA overnight for 48 hours followed by 3 days of cryoprotection in 30% sucrose at 4 degree. Brains were then flash freeze in dry ice and stored in -80 degree Celsius for > 1 week. 20 um sections of the brains were cut using cryostat followed by washing them in TBS solution. Sections were then processed through peroxidase blocking solution followed by sodium borohydrate blocking and finally blocked in blocking buffer (0.3% triton x-100, 10% goat serum, 0.3M Glycine, and anti-mice Affinpure fab fragment). This was followed with incubation with goat anti-rabbit IgG antibody [Alexa Fluor 647 Affini Pure Goat anti-rabbit IgG (H+L)] at room for 1 hour with gentle shaking. Finally, sections were mounted in glass slides and images were obtained using a confocal microscope (Menzie-Suderam et al., 2020).

[0045] The following patents, applications and publications as listed below and throughout this document are hereby incorporated by reference in their entirety herein.Reference listPetereit, H., & Rubbert-Roth, A. (2009). Rituximab levels in cerebrospinal fluid of patients with neurological autoimmune disorders. Multiple Sclerosis Journal, 15(2), 189-192. https: / / doi.org / 10.1177 / 1352458508098268Kouhi A, Pachipulusu V, Kapenstein T, Hu P, Epstein AL, and Leslie A. Khawli LA. Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives Int J MolDocket No. 11605-057W01Sci. 2021 Jun; 22(12): 6442. Published online 2021 Jun 16. doi: 10.3390 / ijms22126442 PMCID: PMC8235515 PMID: 34208575Grabrucker A.M., Ruozi B., Belletti D., Pederzoli F., Forni F., Vandelli M.A., Tosi G. Nanoparticle transport across the blood brain barrier. Tissue Barriers. 2016;4:el 153568. doi: 10.1080 / 21688370.2016.1153568. [PMC free article] [PubMed] [CrossRef] [Google Scholar] Menzie-Suderam*, J., Modi*, J., Xu, H., Bent*, A., Trujillo*, P., Medley*, K., Jimenez*, E., Shen*, J., Marshall, M., Tao, R., Prentice, H. and Wu, J.-Y. Granulocyte-colony Stimulating Factor Gene Therapy as a Novel Therapeutics for Stroke in a Mouse Model. J. Biomed. Sci. (2020). 27:99 https: / / doi.org / 10.1186 / sl2929-020-00692-5. PMID: 33126859;

Claims

Docket No. 11605-057W01CLAIMSWhat is claimed is:

1. A method for delivering an antibody or antigen binding fragment thereof to a brain of a subject, comprising: administering the antibody or antigen binding fragment thereof to an eye of the subject.

2. The method of claim 1, wherein the antibody or antigen binding fragment thereof is administered to the subject using an eye dropper device.

3. The method of claim 1 or 2, wherein the antibody or antigen binding fragment thereof is a hG-CSF antibody.

4. The method of claim 1 or 2, wherein the antibody or antigen binding fragment thereof is lecanemab.

5. The method of claim 1 or 2, wherein the antibody or antigen binding fragment thereof is a monoclonal antibody.

6. The method of claim 1 or 2, wherein the antibody or antigen binding fragment thereof is a polyclonal antibody.

7. The method of claim 1 or 2, wherein the antibody or antigen binding fragment thereof is a human antibody.

8. The method of claim 1 or 2, wherein the antibody or antigen binding fragment thereof is a humanized antibody.

9. The method of claim 1 or 2, wherein the antibody or antigen binding fragment thereof is a chimeric antibody.

10. The method of any one of claims 1 to 9, further comprising the step of detecting the antibody or antigen binding fragment thereof in the brain of the subject.Docket No. 11605-057W0111. A method of treating a brain disease or disorder in a subject, comprising: administering an antibody or antigen binding fragment thereof to an eye of the subject.

12. The method of claim 11, wherein the antibody or antigen binding fragment thereof is administered to the subject using an eye dropper device.

13. The method of claim 11 or 12, wherein the antibody or antigen binding fragment thereof is a hG-CSF antibody.

14. The method of claim 11 or 12, wherein the antibody or antigen binding fragment thereof is lecanemab.

15. The method of claim 11 or 12, wherein the antibody or antigen binding fragment thereof is a monoclonal antibody.

16. The method of claim 11 or 12, wherein the antibody or antigen binding fragment thereof is a polyclonal antibody.

17. The method of claim 11 or 12, wherein the antibody or antigen binding fragment thereof is a human antibody.

18. The method of claim 11 or 12, wherein the antibody or antigen binding fragment thereof is a humanized antibody.

19. The method of claim 11 or 12, wherein the antibody or antigen binding fragment thereof is a chimeric antibody.

20. The method of any one of claims 11 to 19, wherein the brain disease or disorder is selected from Alzheimer’s Disease, Parkinson’s Disease, or a brain cancer.

21. The method of any one of claims 11 to 20, wherein the brain disease or disorder is Alzheimer’s Disease.

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