REFERENCE TO SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled SEQ_LISTING_131819_00204.txt, created and last saved Aug. 13, 2021, which is 12,360 bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.

BACKGROUND

The central nervous system (CNS) and the immune system have very complex interactions that both control and modulate the function of each others1-6. Recent work emphasized the role of T cells in the regulation of cognition in mice7-9. Indeed, mice lacking a functional immune system, notably CD4 T cells, exhibit impaired performance of cognitive tasks. This impairment is rescued by injection of CD4 T cells back into immune deficient mice7. Under normal conditions, T cells are virtually absent from the brain parenchyma but are enriched in the surrounding of the brain called the meninges5,8, notably around the major blood vessels in the dura mater, the sinuses10. It was previously unclear how T cells, localized in the meninges, are able to affect brain function.

Multiple sclerosis (MS) is characterized by the destruction of the CNS myelin and is considered to be an autoimmune disease. MS results in physical, mental, and/or psychiatric problems. Symptoms may include double vision, muscle weakness, trouble with sensation, or trouble with coordination. There is currently no cure for MS.

Alzheimer's disease (AD) is a type of dementia that is associated with memory loss, and problems with thinking and behavior. The parenchymal accumulation of neurotoxic amyloid beta (Aβ) is a central hallmark of AD. There is currently no cure for AD and treatments are limited to reducing and/or slowing the progression of the symptoms.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, verbal and non-verbal communication, and restricted and repetitive behavior. There is currently no cure for ASD. There is a need in the field for methods of treatment for neurological immunity disorders, including but not limited to MS, AD and ASD. The present disclosure addresses this need.

FIELD

Embodiments herein relate to methods for treating, preventing, inhibiting or ameliorating a neurological immunity disorder, or a symptom thereof.

SUMMARY

In some embodiments, the present application provides methods of treating, preventing, inhibiting, delaying the onset of, or ameliorating a neurological immunity disorder or a symptom thereof in an animal subject. The method can comprise administering to the subject a therapeutically effective amount of a compound that inhibits (or blocks) integrin signaling. In some embodiments, methods of treating, preventing, inhibiting, delaying the onset of, or ameliorating a neurological immunity disorder or a symptom thereof in an animal subject are described. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound that decreases or inhibits CD49a function, for example by binding specifically to CD49a. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment which binds CD49a. In some embodiments, the compound that inhibits integrin signaling is administered after the onset of the neurological immunity disorder, for example at least about 8 days after the onset of the neurological immunity disorder, for example at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days, including any range between any two of the listed values, for example, including but not limited to the following ranges which are provided for exemplary purposes only: 5-28 days, 5-21 days, 5-14 days, 5-7 days, 7-28 days, 7-21 days, 7-14 days, 10-28 days, 10-21 days, or 10-14 days. In some embodiments, the administration of the compound after the onset of the neurological immunity disorder reduces clinical symptoms of the neurological immunity disorder, which can be measured, for example, by a clinical score. In some embodiments, the compound that inhibits integrin signaling comprises, consists essentially of, or consists of a CD49a inhibiting (or blocking) antibody.

In some embodiments, the subject is a human. The compound can decrease CD49a function. In some embodiments, the compound comprises, consists of, or consists essentially of an antibody that binds specifically to CD49a, or an antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment is a monoclonal antibody. In some embodiments, the antibody or antigen binding fragment is a human antibody. In some embodiments, the antibody or antigen binding fragment is a humanized antibody. In some embodiments, the antibody or antigen binding fragment is a chimeric antibody. In some embodiments, the compound that inhibits integrin signaling is an antibody or an antigen binding fragment which specifically binds CD49a. By “binds specifically to CD49a” it is understood that the antibody or antigen binding fragment binds preferentially to CD49a compared to other antigens, but there is no requirement that the antibody or antigen binding fragment bind with absolute specificity only to CD49a. In some embodiments, the antibody or antigen binding fragment binds specifically to CD49a compared to other integrins. In some embodiments, the antibody binds specifically to CD49a, and does not exhibit appreciable binding to any of CD49b, CD49c, CD49d, CD49e, and/or CD49f. Without being limited by theory, it is noted that CD49a-f represent the alpha 1 through 6 chains of beta 1 integrins, and as such, CD49a-f have different structures and CD49b-f are not expected to appreciably cross react with any antibody that binds specifically to CD49a. In some embodiments, the antibody does not bind specifically to any of CD49b, CD49c, CD49d, CD49e, and/or CD49f, including combinations of two or more of the listed molecules.

In some embodiments the method further comprises the step of identifying a subject in need of treatment. In certain embodiments the subject in need of treatment is susceptible to or suffering from a neurological immunity disorder selected from the group consisting of autism spectrum disorder (ASD), multiple sclerosis (MS), Alzheimer's disease (AD), and central nervous system (CNS) injury.

In some embodiments, administration of the compound (se.g., an antibody or antigen binding fragment specific for CD49a) is via intracerebroventricular injection. In other embodiments, an ointment comprises the compound and administration is via application of the ointment to the skin (scalp) of said subject. In some embodiments, the ointment comprises the compound and administration is via application of the ointment to the head of the subject, such as on the scalp.

In some embodiments, the administration of the compound (e.g., an antibody or antigen binding fragment specific for CD49a) results in accumulation of immune cells in the brain meninges. In particular embodiments, the administration of the compound results in elevated T cells and natural killer T (NKT) cells in the brain parenchyma.

In some embodiments, the present application provides a method of treating MS in a human subject, comprising administering to the subject a therapeutically effective amount of a CD49a inhibiting (or blocking) antibody or antigen binding fragment thereof. In particular embodiments, the method further comprises the step of identifying a subject in need of said treatment. In other embodiments, the administration of the CD49a inhibiting (or blocking) antibody is via intracerebroventricular injection. In still further embodiments, an ointment comprises said CD49a inhibiting (or blocking) antibody and the administration is via application of the ointment to the skin (scalp) of the subject. In some embodiments, an ointment comprises said CD49a inhibiting (or blocking) antibody and the administration is via application of the ointment to the head of the subject, such as on the scalp.

In some embodiments, the CD49a inhibiting (or blocking) antibody or antigen binding fragment thereof is administered after the onset of the neurological immunity disorder. In some embodiments, the administration of the CD49a inhibiting (or blocking) antibody or antigen binding fragment thereof after the onset of the neurological immunity disorder reduces clinical symptoms of the neurological immunity disorder, which can be measure, for example, by a clinical score.

