Inhibiting NETosis with Nuclear-Penetrating Antibodies

Repurposing nuclear-penetrating autoantibodies from lupus and scleroderma patients as potent, safe inhibitors of pathogenic NETosis.
Ongoing Systemic Diseases Systemic Lupus Erythematosus (SLE) Systemic Sclerosis (Scleroderma) Academia–Industry Partnerships Animal Models Autoantibodies Biological & Mechanistic Collaboration & Innovation Drug Repurposing Experimental Platforms & Models Innate Immunity Therapeutic Development Translational & Clinical

Funding Year: 2024

Project Overview

Neutrophils fight infection by releasing DNA-protein webs called neutrophil extracellular traps (NETs), but dysfunctional NET release drives inflammation and tissue damage in autoimmune diseases. No safe, effective NETosis inhibitors currently exist. This project discovered that certain autoantibodies can enter neutrophil nuclei and interfere with molecular triggers of NETosis — and proposes to repurpose nuclear-penetrating autoantibodies from lupus and scleroderma patients as therapeutic inhibitors. A lead lupus-derived anti-DNA antibody demonstrated the most potent NETosis inhibition among all candidates tested, showed efficacy in vivo, and preserved neutrophil survival and nuclear membrane integrity — establishing a compelling potency and safety profile for clinical development.

Impact & Innovation

Turning autoantibodies into NETosis therapeutics.

 

A lupus-derived anti-DNA antibody has emerged as the most potent NETosis inhibitor tested — preserving neutrophil function while blocking pathogenic NET release, with a Yale startup and 3-year IND pathway already in motion.

  • Identifies nuclear-penetrating autoantibodies as a novel class of NETosis inhibitors, addressing a significant gap where no safe, effective inhibitors currently exist
  • Strengthens existing Yale IP on nuclear-penetrating antibodies with new mechanistic and safety data, with additional IP anticipated from ongoing studies
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar by moving a repurposed autoantibody from mechanistic discovery to startup formation, IND preparation, and Phase I/II trials in ANCA-associated vasculitis
Research Approach

A framework designed for discovery

This project combines autoantibody screening, mechanistic cell biology, and in vivo validation to identify and characterize nuclear-penetrating antibodies as inhibitors of NETosis, with a translational focus on advancing a lead candidate toward clinical development for autoimmune and inflammatory diseases.

Screening of a panel of cell-penetrating lupus and scleroderma autoantibodies for NETosis inhibition potency; in vitro mechanistic studies of nuclear membrane integrity, neutrophil survival, and NETosis trigger interference; and in vivo efficacy testing of the lead anti-DNA antibody candidate as a NETosis inhibitor.

Panel of nuclear-penetrating autoantibodies derived from lupus and scleroderma patients, in vitro neutrophil functional assay datasets measuring NETosis inhibition and neutrophil survival, and in vivo model datasets assessing efficacy and safety of the lead candidate.

Identification and validation of a lead nuclear-penetrating antibody with potent, safe NETosis inhibition activity, elucidation of its mechanisms of action, and advancement toward IND filing and Phase I/II clinical trials in ANCA-associated vasculitis. A new Yale venture startup, Nucleicon, has been founded with an anticipated 3-year path to IND initiation.

Investigators & Institutions

Powering the science

Principal Investigator

James E. Hansen, MD, Colton Consortium Member

Associate Professor, Department of Therapeutic Radiology, Yale School of Medicine, Yale University

Colton Centers & Institutions

Colton Center for Autoimmunity at Yale University

Research Outputs

From insight to impact

Publications

A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells

Science Signalling
Chen, X; Tang, X; Xie, Y; Cuffari, BJ; Tang, C; Cao, F; Gao, X; Meng, Z; Noble, PW; Young, MR; Turk, OM; Shirali, A; Gera, J; Nishimura, RN; Zhou, J; Hansen, JE March 2025
Adaptive ImmunityAnimal ModelsAutoantibodiesBiological & MechanisticDrug RepurposingExperimental Platforms & ModelsIn Vitro ModelsInnate ImmunityTherapeutic DevelopmentTranslational & ClinicalOtherSystemic Lupus Erythematosus (SLE)Yale University

Additional Outputs

  • Yale venture startup Nucleicon founded, with anticipated 3-year path to IND and Phase I/II trial initiation in ANCA-associated vasculitis.
  • Existing Yale IP on nuclear-penetrating antibodies strengthened
  • Supplemental IP anticipated from ongoing mechanistic and safety studies.