Marimastat

Amyloid related imaging abnormalities (ARIA) remain a major obstacle to the widespread use of anti‐amyloid immunotherapy. Data has indicated an association of neuroinflammation and subsequent MMP activation as being associated with anti‐amyloid immunotherapy. We therefore performed a co‐administration study of anti‐amyloid immunotherapy (3D6) with marimastat, an MMP inhibitor that targets MMP1, 2, 3, 7 and 9, with the highest affinity for MMP9.

We initiated treatment with both agents in 19 mo hAbetaSAA knockin mice. Monthly MRI imaging was performed and, upon euthanasia, we performed scRNAseq on the frontal cortex using a glial enrichment preparation, and histological analysis for microhemorrhages.

We found that anti‐amyloid immunotherapy‐mediated Prussian blue microhemorrhages were not significantly reduced by marimastat co‐administration. However, MRI detected microhemorrhages were reduced by marimastat treatment. In our scRNAseq dataset we found significant shifts in microglial state with anti‐amyloid immunotherapy not detected with the control IgG.

MMP inhibition does not appear to impact small microhemorrhages detected histologically. However, the reduced microhemorrhages detected using MRI suggests that marimastat prevented the development of larger sized microhemorrhage events. Data analysis continues to gain further insights from this study.

As patients receive approved anti‐Aβ immunotherapies the critical need to understand the effects of anti‐Aβ antibody exposure on the brain is of extreme priority. We sought to identify immune changes in response to acute and chronic anti‐Aβ antibody to determine potential causes of neuroinflammation that may lead to ARIA (amyloid‐related imaging abnormalities). Further, we investigated whether modifying the activity of MMP9, a key matrix metalloprotease that increases with anti‐Aβ antibody treatment, can reduce anti‐Aβ cerebrovascular disruption.

To understand cellular responses due to acute anti‐Aβ antibody exposure, we intracranially injected 17mo humanized Aβ (hAβ) mice with and without familial amyloid mutations (Swedish, Arctic, Austrian; hAβ SAA ) with anti‐AB 3D6 or control IgG for 3 days (Figure 1). This acute study evaluates early transcriptional changes that occur in glial and peripheral immune cells, using single cell sequencing (SCseq), coupled with spatial transcriptomics to identify acute molecular responses. To evaluate chronic anti‐Aβ exposure, we injected 3D6 intraperitoneally for 3 months starting at 20mo (Figure 2). We evaluated ARIA through longitudinal MRI, cellular responses via SCseq, spatial transcriptomics, and IHC. To investigate the effect of MMP9 inhibition and neuroinflammation on ARIA risk, we co‐injected these mice with Marimastat, a small molecular inhibitor of several MMPs throughout this study.

The acute SCseq study revealed diverse microglial cell states in response to injection (Figure 3, left). There were sex and treatment specific responses of various microglia sub‐populations. There was a sex‐specific effect on the number of differentially expressed genes across microglia subtypes with an emphasis on downregulation of cellular programs, particularly in translation and neuronal support suggesting early responses to anti‐Aβ antibody affects immune cell prioritizations (data not shown). We found stark differences between anti‐Aβ and IgG responses in ligand‐receptor communications involving microglia, suggesting an altered immune response (Figure 3, right). The chronic study analysis is ongoing.

These data lay the groundwork for understanding the brain's unique response to anti‐Aβ antibody and early neuroinflammation.