CSF proteomic analysis of semorinemab Ph2 trials in prodromal-to-mild (Tauriel) and mild-to-moderate (Lauriet) Alzheimer’s disease identifies distinct trial cell-type specific proteomic signatures

Abstract

Targeting of tau pathology has long been proposed as a potential therapeutic strategy for Alzheimer`s disease (AD). Semorinemab is a humanized IgG4 monoclonal antibody that binds to all known isoforms of full-length tau with high affinity and specificity. Semorinemab`s safety and efficacy have been studied in two Phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trials: Tauriel (prodromal-to-mild AD;NCT03289143) and Lauriet (mild-to-moderate AD;NCT03828747). CSF was collected from a subset of patients at baseline and after 49 or 73 weeks in Tauriel and baseline and after 49 or 61 weeks in Lauriet. We generated a large proteomics dataset, using more than 250 cerebrospinal fluid (CSF) samples and detecting more than 3500 proteins, to investigate the effects of semorinemab in each trial. Treatment-induced proteomic signatures were defined for each study as a set of proteins significantly elevated in the treatment arm in the respective study. Integration of the corresponding gene signatures with two independent brain single-nucleus RNA-seq datasets from AD and healthy aged controls revealed that Lauriet signature genes were enriched in microglial cells, while Tauriel signature genes were more broadly expressed across major brain cell types. Furthermore, the Lauriet trial gene signature was significantly upregulated in microglia from AD patients as compared to non-demented controls. The elevation of proteins such as CHI3L1 and GPNMB with treatment suggested an activated glial state. Taken together, this study utilizes a large CSF clinical proteomics dataset to assess the pharmacodynamic response of semorinemab and contributes to our understanding of how an anti-tau antibody influences disease-relevant pathophysiology in AD.

Pharmacodynamic effects of semorinemab on plasma and CSF biomarkers of Alzheimer’s disease pathophysiology

“…At the transcriptomic level, YKL-40 expression is increased in human AD brains, but not with subjects carrying the loss of function R62H TREM2 variant which reduces microglia activation [19]. Additional evidence of a semorinemab effect on microglia activity comes from proteomic analyses of Tauriel and Lauriet CSF, where the post-treatment proteomic signatures indicated that the proteomic response in Lauriet was likely of microglial origin [20]. Together with the CSF YKL-40 observations, these findings were unexpected because semorinemab was developed on an IgG4 backbone, which has been demonstrated to have lower binding affinity to fragment crystallizable gamma receptor (FcR) and expected to have reduced immune effector function [21].…”

“…It decreases in response to anti-amyloid therapy, is associated with plaque removal [17,24,25], and across our Ph2 studies, baseline levels demonstrate a degree of correlation with metrics of cognition and function. The robust CSF YKL-40 response and the unique enrichment of microglia proteins observed in an analysis of the Lauriet CSF proteome [20] suggest an intriguing possibility that the stabilization of plasma GFAP in Lauriet may be a response to microglia activity stimulated by semorinemab. Since semorinemab has no discernable effect on Tau aggregation, our post hoc discovery of microglia activation and variations in plasma GFAP between the trials presents a scientific hypothesis that this biology may account for the discrepancies observed in the trial outcomes.…”