Reducing systemic regulatory t cell levels or activity for treatment of disease and injury of the CNS
The present specification discloses a pharmaceutical composition comprising an active agent that causes reduction of the level of systemic immunosuppression in an individual for use in treating a disease, disorder, condition or injury of the CNS. The pharmaceutical composition is administered by a dosage regimen comprising at least one course of therapy, each course of therapy comprising in sequence a treatment session followed by an interval session of non-treatment.
1. A method of treating a tauopathy to an individual in need thereof, the method comprising administering to the individual a composition comprising a human neutralizing anti-PD-1 antibody, a humanized, neutralizing anti-PD-1 antibody, a human neutralizing anti-PD-L1 antibody, a humanized, neutralizing anti-PD-L1 antibody, a human neutralizing anti-TIM-3 antibody, a humanized, neutralizing anti-TIM-3 antibody, or any combination thereof,
wherein the composition is administered by a dosage regime comprising at least two courses of therapy, each course of therapy comprising in sequence a treatment session where the composition is administered to the individual followed by a non-treatment period where the composition is not administered to the individual,
wherein the non-treatment period is longer than the treatment session;
wherein, if administration of the composition during the treatment session is a repeated administration, the non-treatment period is longer than the period between repeated administrations during the treatment session;
wherein administration of the composition transiently reduces levels of systemic immunosuppression and increases choroid plexus gateway activity in facilitating selective recruitment of immune cells into the central nervous system, thereby treating the individual.
2. The method according to claim 1 , wherein the administration of the composition during the treatment session is a single administration or a repeated administration.
3. The method according to claim 2 , wherein the repeated administration occurs once every day, once every two days, once every three days, once every four days, once every five days or once every six days.
4. The method according to claim 2 , wherein the repeated administration occurs once weekly or once every two weeks, once every three weeks or once every four weeks.
5. The method according to claim 1 , wherein the treatment session is from 1 day to four weeks.
6. The method according to claim 5 , wherein the treatment session is from 3 days to four weeks.
7. The method according to claim 6 , wherein the treatment session is from one week to four weeks.
8. The method according to claim 1 , wherein the non-treatment period is from one week to six months.
9. The method according to claim 8 , wherein the non-treatment period is from two weeks to six months.
10. The method according to claim 9 , wherein the non-treatment period is from three weeks to six months.
11. The method according to claim 10 , wherein the non-treatment period is from one month to three months.
12. The method according to claim 11 , wherein the non-treatment period is from one month to two months.
13. The method according to claim 1 , wherein the transient reduction in the level of systemic immunosuppression is associated with an increase in a systemic presence or activity of IFNγ-producing leukocytes and/or an increase in a systemic presence or activity of an IFNγ cytokine, an increase in a systemic presence or activity of effector T cells, a decrease in a systemic presence or activity of regulatory T cells and/or a decrease in a systemic presence of an IL-10 cytokine, and/or a decrease in a systemic presence or myeloid-derived suppressor cells (MDSCs).
14. The method according to claim 1 , wherein the transient reduction in the level of systemic immunosuppression occurs by release of a restraint imposed on the immune system by one or more immune checkpoints.
15. The method according to claim 14 , wherein administration of the composition blocks the one or more immune checkpoints, thereby causing the transient reduction in the level of systemic immunosuppression.
16. The method according to claim 15 , wherein the one or more immune checkpoints includes a PD1-PD-L1, a PD1-PD-L2, a TIM-3-Gal9 or any combination thereof.
17. The method according to claim 1 , wherein a cerebral level of soluble amyloid beta peptide is reduced in the individual, a cerebral amyloid beta (Aβ) plaque burden is reduced or cleared in the individual, a hippocampal gliosis is reduced in the individual, a cerebral level of a pro-inflammatory cytokine is reduced in the individual, a brain inflammation is decreased in the individual and/or a cognitive function is improved in the individual.
18. The method according to claim 1 , wherein the tauopathy is Alzheimer's disease, argyrophilic grain disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia pugilistica, frontotemporal dementia, frontotemporal lobar degeneration, Hallervorden-Spatz disease, Huntington's disease, ganglioglioma, gangliocytoma, globular glial tauopathy, lead encephalopathy, lipofuscinosis, Lytico-Bodig disease (Parkinson-dementia complex of Guam), meningioangiomatosis, Parkinsonism disease linked to chromosome 17, Pick's disease, primary age-related tauopathy (PART), formerly known as neurofibrillary tangle-only dementia (NFT-dementia), postencephalitic parkinsonism, progressive supranuclear palsy, subacute sclerosing panencephalitis or tuberous sclerosis.
19. The method according to claim 1 , wherein the tauopathy is an Alzheimer's disease.
20. The method according to claim 1 , wherein the tauopathy is a Parkinsonism disease.