Abstract: FR-PO364

A Novel, Highly Specific TGFβ1 Inhibiting Antibody Demonstrates Antifibrotic Activity without Cardiotoxicity

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Wawersik, Stefan, Scholar Rock Inc, Cambridge, Massachusetts, United States
  • Pavlik, Kaleigh, Scholar Rock Inc, Cambridge, Massachusetts, United States
  • Jackson, Justin William, Scholar Rock Inc, Cambridge, Massachusetts, United States
  • Carven, Gregory, Scholar Rock Inc, Cambridge, Massachusetts, United States
  • Buckler, Alan, Scholar Rock Inc, Cambridge, Massachusetts, United States
  • Schurpf, Thomas, Scholar Rock Inc, Cambridge, Massachusetts, United States
  • Datta, Abhishek, Scholar Rock Inc, Cambridge, Massachusetts, United States
  • Littlefield, Christopher, Scholar Rock Inc, Cambridge, Massachusetts, United States
  • Chapron, Christopher, Scholar Rock Inc, Cambridge, Massachusetts, United States
  • Morgan, Kathy Ye, Scholar Rock Inc, Cambridge, Massachusetts, United States
  • Martin, Constance, Scholar Rock Inc, Cambridge, Massachusetts, United States
  • Long, Kimberly, Scholar Rock Inc, Cambridge, Massachusetts, United States
  • Capili, Allan, Scholar Rock Inc, Cambridge, Massachusetts, United States
Background

Transforming growth factor-β1 (TGFβ1) has diverse biological functions, including regulation of immune response and tissue homeostasis. TGFβ1 activation has been associated with diseases including kidney fibrosis, where chronic activation is a key driver. Because of high homology between the TGFβ1 growth factor and its close relatives TGFβ2 and TGFβ3, truly TGFβ1-specific inhibitors have remained elusive. Pan-TGFβ inhibition, on the other hand, can cause dose-limiting heart valvulopathies, leading to concerns with long-term dosing. TGFβs are expressed as pro-proteins that are proteolytically cleaved into a C-terminal growth factor and an N-terminal prodomain that remains noncovalently associated with the growth factor, preventing receptor binding. This latent TGFβ complex resides on cells or in the extracellular matrix until it is activated by integrins, freeing the growth factor and allowing receptor binding.

Methods

To identify TGFβ1-specific antibodies, we targeted the prodomain, which shares much lower homology to TGFβ2 and TGFβ3 than the growth factor.

Results

We identified SR-AB1, a monoclonal antibody that binds latent TGFβ1 with no detectable binding to latent TGFβ2 or TGFβ3. SR-AB1 blocks latent TGFβ1 activation by αVβ6 or αVβ8 integrins, providing specificity unachieved by biologics that target the TGFβ1 growth factor/receptor interaction. SR-AB1 further inhibits latent TGFβ1 complexed with all four known TGFβ-presenting molecules, allowing targeting of TGFβ1 in multiple tissues. SR-AB1 blocks activation of endogenous TGFβ1 in a number of primary cells, including dermal myofibroblasts and hepatic stellate cells. Critically, while pan-TGFβ inhibitors show evidence of valvulopathy or other cardiotoxicity, SR-AB1 is free of such toxicities in 1 and 4 week rat studies. Finally, we tested the in vivo efficacy of TGFβ1 inhibition via this novel mechanism in the UUO model of kidney fibrosis, showing that SR-AB1 suppresses fibrosis to levels similar to those achieved by pan-TGFβ inhibition.

Conclusion

Our data show that isoform-specific inhibition of latent TGFβ1 is efficacious in a preclinical fibrosis model and has a superior safety profile compared to pan-TGFβ inhibition.

Funding

  • Commercial Support