Poster Exhibition - TGFb for Immuno-Oncology Drug Development

Systemic administration of monovalent follistatin-like 3-Fc-fusion protein increases muscle mass in mice

Authors

Masato Morikawa, Takayuki Ozawa, and Kohei Miyazono - Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Japan

Abstract

Targeting the signaling pathway of growth differentiation factor 8 (GDF8), also known as myostatin, has been regarded as a promising strategy to increase muscle mass in the elderly and in patients with cancer cachexia. Accumulating evidences in animal models and clinical trials have indicated that a rational approach is to inhibit certain members of the transforming growth factor β (TGF-β) family ligands, including GDF8 and activin A, without affecting other members, such as BMPs. Thus, we focused on one of the endogenous antagonists against the TGF-β family ligands, follistatin-like 3 (FSTL3). FSTL3 mainly binds and neutralizes activins, GDF8, and GDF11. Although bivalent human FSTL3 Fc-fusion protein was rapidly cleared from mouse circulation, similar to follistatin (FST)-Fc, monovalent FSTL3-Fc (mono-FSTL3-Fc) generated with the knobs-into-holes technology exhibited longer serum half-life. Systemic administration of mono-FSTL3-Fc in mice induced muscle fiber hypertrophy and increased muscle mass in vivo. Our results indicate that the monovalent FSTL3-based therapy overcomes the difficulties of current anti-GDF8 therapies.

Download Poster

Ask the Author

Production of type III collagen (PRO-C3) by activated fibroblasts is regulated by TGF-β and associates with poor response to immune checkpoint inhibitors when measured in serum

Authors

Nicholas Willumsen, Neel I. Nissen, Christina Jensen, Morten A. Karsdal - Nordic Bioscience, Biomarkers & Research, Herlev, Denmark

Abstract

TGF-β signaling, and related pathways, are major inducers of fibrogenesis. Tumor fibrosis subtypes predict response to immunotherapy. Tumor fibrosis is characterized by fibroblast activation and fibrillar collagen deposition. A fibrillar collagen-rich tumor stroma leads to T-cell exclusion. Type III collagen is a major fibrillar collagen. Production of type III collagen can be measured non-invasively with PRO-C3. Here we show that PRO-C3 is regulated by TGF-β in activated fibroblasts in vitro and associates with poor response to immune checkpoint inhibitors when measured in serum. PRO-C3 may indicate anti-TGF-β and anti-fibrotic effects and benefit patient's outcome.

Download Poster

Ask the Author