Transcriptomic and Proteomic Assessment of Tocilizumab Response in a Randomized Controlled Trial of Patients Hospitalized With COVID-19

Authors

Haridha Shivram
Jason A Hackney
Carrie M Rosenberger
Anastasia Teterina
Aditi Qamra
Olusegun Onabajo
Jacqueline McBride
Fang Cai
Min Bao
Larry Tsai
Aviv Regev
Ivan O Rosas
Rebecca N Bauer

Publication Date

9-15-2023

Journal

iScience

DOI

10.1016/j.isci.2023.107597

PMID

37664617

PMCID

PMC10470387

PubMedCentral® Posted Date

8-11-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Pharmaceutical science, Virology, Omics

Abstract

High interleukin (IL)-6 levels are associated with greater COVID-19 severity. IL-6 receptor blockade by tocilizumab (anti-IL6R; Actemra) is used globally for the treatment of severe COVID-19, yet a molecular understanding of the therapeutic benefit remains unclear. We characterized the immune profile and identified cellular and molecular pathways modified by tocilizumab in peripheral blood samples from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial of the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19. We identified markers of inflammation, lymphopenia, myeloid dysregulation, and organ injury that predict disease severity and clinical outcomes. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab and identified novel pharmacodynamic biomarkers. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysregulation associated with severe COVID-19, indicating greater anti-inflammatory activity relative to placebo and potentially leading to faster recovery in patients hospitalized with COVID-19.

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