Targeting the Cytokine Activin A for the Treatment of Rheumatoid Arthritis

Developing 10E5-1, an anti-activin A antibody delivered via mRNA-LNP, to suppress pathogenic antibody production and treat rheumatoid arthritis through a novel mechanism.
Ongoing Rheumatoid Arthritis Systemic Diseases Animal Models Autoantibodies B Cell Biology Biological & Mechanistic Cytokine Signaling Experimental Platforms & Models T Cell Biology Therapeutic Development Translational & Clinical

Funding Year: 2023

Project Overview

Rheumatoid arthritis affects approximately 25% of patients who do not respond to current treatments, and the cytokine activin A — elevated in RA — has been identified as a regulator of autoantibody production. This project developed 10E5-1, an anti-activin A antibody, and demonstrated that it prevents severe RA development even in mice with established mild disease, matches the efficacy of the proteasome inhibitor Bortezomib, and works downstream of pathogenic antibody production. The antibody was successfully delivered via mRNA-LNP, offering a cost-effective and durable delivery alternative. These findings establish 10E5-1 as a novel therapeutic with platform potential across autoimmune diseases driven by activin A elevation and autoantibody production, including SLE.

Impact & Innovation

A new mechanism for suppressing autoantibody-driven disease.

 

10E5-1 blocks activin A to suppress Tfh cell-driven pathogenic antibody production — working both prophylactically and in established disease, and matching Bortezomib efficacy through an entirely novel mechanism of action.

  • Demonstrates that activin A blockade suppresses Tfh cell differentiation and pathogenic antibody production, establishing a new therapeutic axis applicable to RA, SLE, and other autoantibody-driven diseases
  • Generates IP through a patent application filed May 2025 for compositions and methods of inhibiting activin A activity in autoimmune diseases, with additional Colton funding secured to expand the work
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar by moving a novel cytokine target from mechanistic discovery through mRNA-LNP delivery optimization toward preclinical validation in multiple autoimmune disease models
Research Approach

A framework designed for discovery

This project combines antibody engineering, mRNA-LNP delivery, and preclinical RA and SLE mouse modeling to develop and validate 10E5-1 as a therapeutic targeting activin A-driven pathogenic antibody production. The work moves from mechanism elucidation through delivery optimization and disease model validation.

Development and testing of recombinant anti-activin A antibody 10E5-1; mRNA-LNP formulation and delivery of 10E5-1 as a cost-effective alternative to recombinant antibody administration; prophylactic and therapeutic mouse model studies in RA; combination studies with Bortezomib; IgG transfer experiments to test downstream effects on pathogenic antibody production; and Tfh cell differentiation assays to characterize the mechanism of activin A blockade.

RA mouse model datasets measuring arthritis severity under prophylactic and therapeutic 10E5-1 treatment; mRNA-LNP pharmacokinetic and expression data; IgG transfer experiments from 10E5-1-treated and vehicle-treated mice; Tfh cell functional assay data; and combination treatment datasets with Bortezomib assessing plasma cell generation and survival.

RA mouse model datasets measuring arthritis severity under prophylactic and therapeutic 10E5-1 treatment; mRNA-LNP pharmacokinetic and expression data; IgG transfer experiments from 10E5-1-treated and vehicle-treated mice; Tfh cell functional assay data; and combination treatment datasets with Bortezomib assessing plasma cell generation and survival.

Investigators & Institutions

Powering the science

Principal Investigator

Michela Locci, PhD, Colton Consortium Member

Associate Professor, Department of Microbiology, Perelman School of Medicine, University of Pennsylvania

Colton Centers & Institutions

Colton Center for Autoimmunity at the University of Pennsylvania

Perelman School of Medicine

Research Outputs

From insight to impact

Additional Outputs

Additional Colton Center funding awarded to continue 10E5-1 research and expand to SLE mouse models.

Patent application filed 5/23/2025: Compositions and Methods of Inhibiting Activin-A Activity in Autoimmune Diseases.

Manuscript in preparation; submission planned Fall 2025.