Targeted Biologic Therapy for Autoimmune Disease Associated with DNAseIL3 Deficiency

Developing a bioavailable DNAseIL3 biologic to degrade pathogenic autoantibodies and treat lupus and related autoimmune diseases.
Ongoing Rheumatoid Arthritis Systemic Diseases Systemic Lupus Erythematosus (SLE) Systemic Sclerosis (Scleroderma) Vasculitis Academia–Industry Partnerships Animal Models Autoantibodies Bioinformatics Biological & Mechanistic Clinical Trials Collaboration & Innovation Data-Driven & Quantitative Experimental Platforms & Models Human Genetics Therapeutic Development Translational & Clinical

Funding Year: 2024

Project Overview

Deficiencies in DNAseIL3 — an enzyme that digests extracellular DNA — are genetically linked to lupus, rheumatoid arthritis, and scleroderma, and correlate with severe disease in SLE patients. This project develops a novel biologic therapy targeting DNAseIL3 to restore this degradation function and prevent autoantibody-driven organ damage. A potent, bioavailable DNAseIL3 biologic demonstrated efficacy in mouse models, and GWAS analysis using the UK Biobank confirmed DNAseIL3 as a causal driver of lupus and other autoimmune disorders. Ten candidates have advanced to in silico testing, with a lead drug candidate expected by July 2025 and Phase 1 clinical data targeted by late 2027.

Impact & Innovation

A validated enzyme target with a clear path to clinic.

 

GWAS analysis independently confirmed DNAseIL3 as a causal driver of lupus and related autoimmune diseases — and a $10M venture investment and active CMC development signal strong translational momentum toward Phase 1 trials.

  • Establishes DNAseIL3 as a druggable causal target across lupus, lupus nephritis, rheumatoid arthritis, scleroderma, and ANCA vasculitis, validated through Mendelian randomization of UK Biobank data
  • Generates significant IP potential through a provisional patent for dual-acting DNAse1/DNAseIL3 enzymes with enhanced bioavailability, with filing expected Q3 2025
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar by moving a genetically validated target from mouse efficacy through CMC development toward Phase 1 clinical trials
Research Approach

A framework designed for discovery

This project combines genetic validation, protein engineering, and preclinical drug development to advance a DNAseIL3-targeting biologic from mechanistic discovery to clinical candidacy. The work integrates population genetics, in silico optimization, and manufacturing development to build a translatable therapeutic.


Mendelian randomization analysis of GWAS data from the UK Biobank to validate DNAseIL3 as a causal disease target; sequence optimization of the final human DNAseIL3 clone using in silico tools at Lonza; Chemistry, Manufacturing, and Controls (CMC) development for six of the most active candidates; and cell line development for clinical-grade biologic production.

UK Biobank GWAS data analyzed via Mendelian randomization, mouse models of lupus for preclinical efficacy and survival endpoints, in silico stability and immunogenicity screening datasets, and CMC development data from Lonza for lead candidate characterization.


Identification and optimization of a lead DNAseIL3 biologic candidate with demonstrated stability, manufacturability, and immunogenicity equivalent to approved monoclonal antibodies, advancing toward Phase 1 clinical testing. A provisional patent for dual-acting DNAse1/DNAseIL3 enzymes is planned for Q3 2025, with Phase 1 top-line data targeted by late 2027.

Investigators & Institutions

Powering the science

Principal Investigator

Demetrios Braddock, MD, PhD, Colton Consortium Member

Professor, Department of Pathology, Yale School of Medicine, Yale University

Colton Centers & Institutions

Colton Center for Autoimmunity at Yale University

Research Outputs

From insight to impact

Venture Capital investment: Rheumalogics formed with $10M investment from Novo Holdings.

  • Phase 1 clinical trial in preparation
  • CMC development underway at Lonza (began April 2025), with Phase 1 top-line data targeted by late 2027

Provisional patent application for dual-acting DNAse1/DNAseIL3 enzymes with enhanced bioavailability and activity — filing expected Q3 2025.