Etrolizumab Reduces Genes Associated with Inflammation in Ulcerative Colitis Patients

Jacqueline M. McBride, PhD

In data presented during the 2021 Digestive Disease Week (DDW), a team, led by Jacqueline McBride, Genentech, evaluated post-etrolizumab treatment changes in inflammatory cells, activated fibroblasts, and epithelial cell subsets in intestinal biopsies from ulcerative colitis patients treatment with an induction regimen of etrolizumab.

Etrolizumab is a fully-humanized anti-β7 antibody that blocks α4β7 bearing lymphocytes from interactions with endothelial MADCAM as well as αEβ7 bearing lymphocytes binding to intestinal epithelial E-Cadherin, leading many to believe etrolizumab reduces infiltration and retention of pro-inflammatory β7-bearing immune cells in the gut.

“The etrolizumab trials were part of the largest global clinical trial program ever undertaken in inflammatory bowel disease,” McBride said in an interview with HCPLive®.

Sample Collection

The researchers collected colonic biopsy pairs at baseline and post-treatment from patients participating in 2 open-label induction phase 3 trials of etrolizumab—LAUREL (TNF-naïve UC) and HICKORY (TNF-experienced UC).

The team performed RNA sequencing for 270 pre-post biopsy pairs from the LAUREL study at week 10 and 110 pairs from the HICKORY trial at week 14.

In addition, the researchers compared the pre- and post-treatment pre-defined sets, including those representing specific inflammatory immune cell subsets, activated fibroblasts, and epithelial cell types.

Genes with an estimated fold change of at least 1.5 (multiplicity adjusted P ≤0.05 was considered differentially expressed. The team also evaluated differences in gene expression changes between modified Mayo Clinic score (mMCS) remitters and non-remitters.

They defined remission using a mMCS of at least 2 with individual subscores for endoscopy and stool frequency of at least 1 and a rectal bleeding subscore of 0.

Results

The treatment resulted in a significant reduction in expression of genes representing T & B lymphocytes, plasma cells/plasmablasts, and myeloid cells following induction relative to baseline in both trials at the earmarked time period. They also found the expression of genes associated with activated fibroblasts was significantly reducing following induction with etrolizumab.

The extent of changes in gene expression was strongly linked with mMCS in both the LAUREL and HICKORY cohorts and the expression of genes association with epithelial cell subsets and anti-microbial function was elevated. This indicates epithelial regeneration coupled to the reduced inflammatory burden.

The differentially expressed genes in the 2 studies were similar, with 96% of differentially expressed genes in HICKORY being also differentially expressed in LAUREL.

“In the abstract, we observed a reduction in the expression of genes associated with inflammation, inflammatory immune cells, and activated fibroblasts, as well as an increase in markers associated with epithelial cells in etrolizumab-treated ulcerative colitis (UC) patients,” McBride said. “These changes were associated with modified Mayo Clinic score (mMCS) remission for both TNF-naive and TNF-experienced patients.”

The Future

McBride said there remains a need for future studies involving etrolizumab.

“The results for the Phase III etrolizumab UC studies were mixed as an induction therapy, and not statistically significant as a maintenance therapy,” she said. “Additional assessments will be applied for replication using data from the pivotal UC cohorts. In addition, Phase III studies will continue to evaluate the safety and efficacy of etrolizumab in moderate to severe Crohn’s disease.”

The study, “Resolution in Gene Signatures Associated with Inflammatory Immune Cell Infiltrates, Activated Fibroblasts and Epithelial Recovery in TNF-Naïve and TNF-IR UC Patients Treated with Etrolizumab,” was published online by DDW.