Isoform-selective TGF-β3 inhibition for systemic sclerosis.

Area of Science:

• Immunology
• Fibrosis Research
• Drug Development

Background:

• Transforming growth factor beta (TGF-β) is a key mediator of fibrosis, but its broad functions complicate therapeutic targeting.
• TGF-β has three isoforms (TGF-β1, TGF-β2, TGF-β3) with distinct expression and activation patterns.
• Selective inhibition of TGF-β2 and TGF-β3 has shown potential for fibrosis treatment without significant inflammation.

Purpose of the Study:

• To investigate the role of TGF-β3 in systemic sclerosis (SSc).
• To develop and characterize a selective TGF-β3 inhibitor for potential SSc therapy.

Main Methods:

• Transcriptomic profiling of SSc patient skin biopsies.
• Antibody humanization, biochemical characterization, and crystallization.
• Pre-clinical in vivo and toxicology studies of an anti-TGF-β3 antibody.

Main Results:

• TGF-β3 expression in SSc skin correlates with disease severity and TGF-β signaling biomarkers.
• A potent and selective anti-TGF-β3 monoclonal antibody was developed, demonstrating effective fibrosis attenuation in vivo.
• Toxicology studies indicate a favorable safety profile for chronic administration compared to pan-TGF-β inhibitors.

Conclusions:

• Targeting TGF-β3 is a viable therapeutic strategy for SSc.
• The developed anti-TGF-β3 antibody exhibits a favorable therapeutic index for treating SSc.