TGFβ1

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Ligands
TGFβ1 (Human)

GtoPdb Ligand ID: 5060

Synonyms: TGF-beta-1 | transforming growth factor beta-1

Compound class: Endogenous peptide in human, mouse or rat

Comment: TGFβ is a labile (half-life in vivo of 2-3 minutes) but highly potent cytokine. It plays a crucial role in immune regulation, and is highly fibriogenic.

The TGFβ1 gene encodes a proprotein that contains sequences for the latency-associated peptide (LAP) and the TGFβ peptide chains. Amino acids 1-29 form the signal peptide, 30-278 represent LAP and the C-terminal amino acids from 279-390 form TGFβ.

TGFβ is expressed at the cell surface (e.g. on Treg cells) as a highly glycosylated, furin-processed product in complex with the LAP protein. This complex does not have biological activity (so is a.k.a. latent TGFβ) and requires further processing to produce active TGFβ [4,6].

Species: Human

Immunopharmacology Comments
LAP/TGFβ-expressing Treg cells have been identified in models of oral tolerance [5] and autoimmune disease [1]. In cancers intratumoural Tregs upregulate expression of immunosuppressive molecules, including LAP/TGFβ, as one of the mechanisms that dampens the anti-tumour immune response. Anti-LAP monoclonal antibodies are expected to provide a novel approach for cancer immunotherapy. Antibody binding to LAP on LAP/TGFβ-expressing cells in the tumour microenvironment (e.g. MDSCs, Tregs, and TAMs) directs them for removal, and inhibits the release of TGFβ from LAP/TGFβ complexes [2]. Anti-LAP biologics are predicted to target multiple immunoregulatory pathways to re-activate the immune system across a wider range of cancer types than existing immuno-oncology therapeutics. For example, see the claims in patent WO2016115345A1 'Treatment of cancer with anti-lap monoclonal antibodies' [7]. Inhibiting LAP/TGFβ degradation may also provide beneficial effects in fibrotic diseases, given TGFβ's powerful fibrogenic action, as well as in autoimmune diseases.

Immunopharmacology Comments

LAP/TGFβ-expressing Treg cells have been identified in models of oral tolerance [5] and autoimmune disease [1]. In cancers intratumoural Tregs upregulate expression of immunosuppressive molecules, including LAP/TGFβ, as one of the mechanisms that dampens the anti-tumour immune response. Anti-LAP monoclonal antibodies are expected to provide a novel approach for cancer immunotherapy. Antibody binding to LAP on LAP/TGFβ-expressing cells in the tumour microenvironment (e.g. MDSCs, Tregs, and TAMs) directs them for removal, and inhibits the release of TGFβ from LAP/TGFβ complexes [2]. Anti-LAP biologics are predicted to target multiple immunoregulatory pathways to re-activate the immune system across a wider range of cancer types than existing immuno-oncology therapeutics. For example, see the claims in patent WO2016115345A1 'Treatment of cancer with anti-lap monoclonal antibodies' [7].
Inhibiting LAP/TGFβ degradation may also provide beneficial effects in fibrotic diseases, given TGFβ's powerful fibrogenic action, as well as in autoimmune diseases.