Study of TGF-β1 in Fibrosis Progression: An Exploration of an Antibody Targeting Binding Proteins

Research Background

Fibrosis is a leading cause of poor prognosis in numerous diseases, such as chronic kidney disease, non-alcoholic steatohepatitis, and idiopathic pulmonary fibrosis. Despite the substantial medical need, directly targeting fibrosis progression has remained challenging. Among these challenges, the transforming growth factor-β (TGF-β) pathway is a core molecular mechanism driving fibrosis, with its potential efficacy in pulmonary, hepatic, and renal fibrosis corroborated by multiple preliminary clinical studies. However, safely targeting the TGF-β pathway has always been a challenge. Currently, antibodies or kinase inhibitors targeting all three homologous TGF-β growth factors (TGF-β1, TGF-β2, and TGF-β3) or their common receptor have caused severe cardiovascular valvular lesions in rodent and primate models. This has limited the dosage and further development of clinical research in this area. Nevertheless, targeting the TGF-β pathway still holds potential, with subsequent treatment approaches focusing on more selective strategies to reduce safety concerns.

Research Origin

This study was initiated by Justin W. Jackson and others, from Scholar Rock and ToxStrategies LLC. The research findings were published on July 9, 2024, in the journal Science Signaling (Sci. Signal.).

Research Process

The study involved the following steps:

a) Investigating the role of fibrosis in various diseases, particularly focusing on the TGF-β pathway; b) Developing a selective antibody capable of binding and inhibiting the activation of TGF-β1 presented by latent TGF-β-binding proteins (LTBPs); c) Evaluating the safety and efficacy of this antibody in a rodent renal fibrosis model; d) Clarifying the selectivity of the antibody through structural studies and proposing possible mechanisms of action.

Research Findings

The study found that the antibody LTBP-49247 can specifically bind and inhibit LTBP-presented TGF-β1 activation without binding to GARP or LRRC33-presented TGF-β1. Based on the LRRs structure, the selectivity of LTBP-49247 may arise from specific recognition of LTBP-presented components in the latent complex of TGF-β1. In two different etiology rodent renal models, LTBP-49247 slowed down the progression of fibrosis. Additionally, no traditional toxicities related to TGF-β pathway inhibitors were observed in the 13-week-long mouse toxicity study.

Research Conclusion and Significance

This study demonstrates that by specifically inhibiting TGF-β1 pathways presented by binding proteins, safe and effective fibrosis treatment can be achieved. This offers a new direction for TGF-β pathway treatments, potentially avoiding the safety risks of previous non-selective TGF-β inhibitors. LTBP-49247 showed good safety and promising anti-fibrotic activity, suggesting it could become an important drug for treating fibrotic diseases in the future.

Research Highlights

• LTBP-49247 is effective only for LTBP-presented TGF-β1, providing high selectivity;
• Compared to antibodies targeting all types of TGF-β1, it avoids safety risks such as valve disease;
• It shows anti-fibrotic effects in different etiology models of renal fibrosis, indicating a universal mechanism of action;
• Traditional toxicities of TGF-β pathway inhibitors were not observed after long-term multiple administrations.

Other Points of Interest

Furthermore, further development of TGF-β1 therapeutic strategies presented by LTBPs may require understanding the context of different TGF-β1 expression levels and fibrosis pathological states, providing personalized treatments for diseases. Additionally, other potential clinical applications, such as cancer immunotherapy, await further exploration.