Targeting aVb8 integrin to restore astrocyte-microglia crosstalk to treat Alzheimer's disease

PHASE I APPLICATION (STTR Program PAS-22-197) “Targeting aVb8 integrin to restore astrocyte-microglia crosstalk to treat Alzheimer’s disease” ABSTRACT Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays a significant role in the onset and progression of the disease. We previously identified a central role for TGFβ5 and the TGFb-activating integrin, aVb8 (ITGB8), in regulating and developing homeostatic microglia6. We recently discovered that ITGB8 is highly expressed on astrocytes in patients with AD, especially those expressing APOE4, the strongest genetic risk factor for AD6, and that ITGB8 expression is associated with increased TGFb signalling in neurodegenerative microglia (MGnD)7, also known as disease-associated microglia (DAM)8. Mechanistically, we found that an APOE4-ITGB8-TGFb pathway impairs microglia-astrocyte response to AD pathology7, and that blocking ITGB8 in AD mouse models restores microglial to a neuroprotective MGnD state8- 10, which mitigates pathology and improves cognition7. The major question relates to microglia-based approach to treat AD is how to modulate microglia phenotype and function. Preservation of neuronal cells from Aβ induced apoptosis as well as restoration of resident microglial homeostatic function is critical for the brain function. The goal of this proposal is to test whether pharmacological inhibition of ITGB8 with a new humanized mAb, ADWA11, can safely and effectively restore microglia-astrocyte responses as a therapy for AD, that will lead to development of novel AD treatment. An early version of ADWA11 is currently in Phase 1 clinical trial to treat solid tumors (Clinical Trial: NCT04152018), which has been well-tolerated in humans. Our preliminary data demonstrated that systemic administration of humanized ITGB8-blocking antibody enhances an MGnD phenotype, ameliorates AD pathology, and improves cognition. We propose a multidisciplinary approach integrating novel tools, experimental paradigms, and deep expertise in microglia (Oleg Butovsky, Brigham and Women's Hospital/Harvard Medical School), blood-brain barrier (BBB) and astrocytes and integrin biology (Thomas Arnold, UCSF), to determine the efficacy and safety of a novel high-affinity human ITGB8-blocking mAb, ADWA11, to restore microglial functions as a treatment for AD. We will address our hypothesis with the following aims: Aim 1: Determine targeting kinetics of hADWA11 to induce MGnD phenotype in human iPSC-derived astrocyte-microglia crosstalk. Aim 2: Establish PK/PD, biodistribution, and target engagement for hADWA11 in APOE4:5xFAD AD mice. Aim 3: Determine whether chronic systemic treatment with hADWA11 can ameliorate cognitive impairment and neurodegeneration in humanized APOE4:5xFAD mice. Based on the results of this work we will be able to develop a first in class antibody-based treatment to restore microglial functions for treatment of Alzheimer’s disease, and particularly for AD APOE4 carriers.