Non-Invasive Delivery of IL-2 to the CNS for Local Expansion of Regulatory T Cells and Prevention of Neurodegeneration in Tauopathy

There is a growing recognition that the immune system plays a key role in damaging brain cells during the progression of Alzheimer’s disease. While the immune system is normally protective against foreign invaders such as viruses or bacteria, it can become dysregulated in diseases such as Alzheimer’s disease, attack neurons, and cause neurodegeneration. One attractive approach to counter these harmful effects is to promote beneficial immune responses, especially by increasing the number of regulatory T cells in the brain that secrete anti-inflammatory signals and prevent immune cells from harming neurons and other brain cells. The most effective agent for expanding regulatory T cells is a small immune protein called IL-2. However, it has been challenging to deliver IL-2 to the brain after injection into the bloodstream for several reasons, including that it is rapidly cleared from the bloodstream within minutes after administration and cannot cross the blood-brain barrier and enter the brain. To address these challenges, we propose to fuse IL-2 to two binding proteins known as antibodies or antibody fragments, resulting in fusion proteins referred to as bispecific antibody-IL-2 (bAb-IL2) or immunocytokines. The first antibody fragment recognizes a specific protein (CD98hc) at the blood-brain barrier, facilitating the transport of bAb-IL2 across this barrier and into the brain. The second full-length antibody targets a highly expressed and brain-specific protein (myelin oligodendrocyte glycoprotein, MOG), which ensures strong brain localization and long-lived retention of bAb-IL2 in the brain. We expect that brain delivery and retention of IL-2 using bAb-IL2 fusion proteins will i) increase the number of regulatory T cells in the brain and ii) reduce damage to brain cells caused by immune cells in a mouse model associated with Alzheimer’s disease. To test this hypothesis, in Aim 1, we will generate the bAb-IL2 proteins and evaluate their ability to i) pass through the intact blood-brain barrier in mice and enter the brain, ii) bind to a brain-specific protein (MOG) and accumulate in the brain, and iii) increase the number of regulatory T cells in the brain. Next, in Aim 2, we will administer the bAb-IL2 fusion proteins to mice that overexpress a human protein (tau) linked to Alzheimer’s disease and evaluate if this treatment prevents neurodegeneration, neuroinflammation, and cognitive impairment. These experiments will provide a key proof-of-concept test of the ability of IL-2 to induce regulatory T cells in the brain and protect against neurodegeneration in a pre-clinical animal model, which is a key step toward the development of therapeutics that can be tested in humans.