Isoform-selective TGF-β3 inhibition for systemic sclerosis.

Publication Type:

Journal Article


Med, Volume 5, Issue 2, p.132-147.e7 (2024)


Fibrosis, Humans, Protein Isoforms, Scleroderma, Systemic, Transforming Growth Factor beta1, Transforming Growth Factor beta2, Transforming Growth Factor beta3


<p><b>BACKGROUND: </b>Transforming growth factor β (TGF-β) is implicated as a key mediator of pathological fibrosis, but its pleiotropic activity in a range of homeostatic functions presents challenges to its safe and effective therapeutic targeting. There are three isoforms of TGF-β, TGF-β1, TGF-β2, and TGF-β3, which bind to a common receptor complex composed of TGF-βR1 and TGF-βR2 to induce similar intracellular signals in&nbsp;vitro. We have recently shown that the cellular expression patterns and activation thresholds of TGF-β2 and TGF-β3 are distinct from those of TGF-β1 and that selective short-term TGF-β2 and TGF-β3 inhibition can attenuate fibrosis in&nbsp;vivo without promoting excessive inflammation. Isoform-selective inhibition of TGF-β may therefore provide a therapeutic opportunity for patients with chronic fibrotic disorders.</p><p><b>METHODS: </b>Transcriptomic profiling of skin biopsies from patients with systemic sclerosis (SSc) from multiple clinical trials was performed to evaluate the role of TGF-β3 in this disease. Antibody humanization, biochemical characterization, crystallization, and pre-clinical experiments were performed to further characterize an anti-TGF-β3 antibody.</p><p><b>FINDINGS: </b>In the skin of patients with SSc, TGF-β3 expression is uniquely correlated with biomarkers of TGF-β signaling and disease severity. Crystallographic studies establish a structural basis for selective TGF-β3 inhibition with a potent and selective monoclonal antibody that attenuates fibrosis effectively in&nbsp;vivo at clinically translatable exposures. Toxicology studies suggest that, as opposed to pan-TGF-β inhibitors, this anti-TGF-β3 antibody has a favorable safety profile for chronic administration.</p><p><b>CONCLUSION: </b>We establish a rationale for targeting TGF-β3 in SSc with a favorable therapeutic index.</p><p><b>FUNDING: </b>This study was funded by Genentech, Inc.</p>