Identification, Characterization, and Correction of a Defect in Treg Function in SLE
Abstract
The goal of our grant is to develop a protein drug conjugate that can be used to restore function to defective Tregs of autoimmune patients. We previously showed the Tregs of autoimmune patients, including SLE patients, share a common defect in IL-2R signaling. This defect may be restored using neddylation activating enzyme inhibitors (NAEi), however, NAEi are toxic when used systemically. To reduce toxicity, we developed a protein drug conjugate (PDC) consisting of a fusion protein of murine thioredoxin and IL-2 to which three molecules of the NAEi MLN4924 were conjugated through a dipeptide cleavable linker. This mouse PDC(mPDC) was effective in preventing disease in various mouse models of autoimmunity. The purpose of the current grant is to develop a human version of the PDC that can be used to restore function in the defective Tregs of SLE patients, and to develop a diagnostic assay that can be used to identify SLE patients with defective Tregs who may respond to PDC treatment. During this first year of funding we developed 5 different human PDCs and tested the efficacy of these drugs in various assays. Several were selected for additional in vivo and in vitro testing. We identified a single lead candidate. The effectiveness of this drug in restoring or enhancing Treg activity in SLE patients will be tested in the second year of funding. We have also made progress in developing potential diagnostic assays that maybe used for identifying individuals who have a defect in IL-2R signaling. The first assay is based on the protein expression of GRAIL and ARF1, a protein that stabilizes GRAIL. Custom antibodies for GRAIL and ARF1 have been made, and will be tested in the second year of funding. The second potential diagnostic assay is based on the mRNA expression of an alternatively spliced variant of GRAIL.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2023
- Accession Number
- AD1209666
Entities
People
- Charles G. Fathman
Organizations
- Stanford University