The discovery is a group of novel pan-TGF-beta inhibitor fusion proteins that bind TGF-betas with higher affinity than other compounds currently in preclinical and clinical studies. This TGF-beta antagonist may be useful for treating and/or ameliorating cancer, especially at the metastatic stages.
Background:
TGF-beta is a potent growth inhibitor in normal epithelial cells by inducing cell cycle arrest, cell senescence, and/or apoptosis. The loss of the inhibitory effect of TGF-beta may lead to uncontrolled cell proliferation and the development of cancer. This effect may occur by a number of mechanisms including mutations in TGF-beta signaling pathway itself or dysregulation of cell cycle and survival machinery .
Increased TGF-beta expression is strongly associated with the progression of many cancers and often leads to a poor clinical outcome. TGF-beta also contributes to cancer development by suppressing host immune surveillance and acting as an angiogenic factor which promotes metastasis to various organs. As such the TGF-beta signaling pathway represents an important molecular target for the development of novel therapeutic agents for the treatment of cancer.
Several approaches at inhibiting this signaling pathway have been explored including both intracellular and extracellular targets. Though a number of TGF-beta inhibitors have been reported, none have been approved for clinical use, and some have reported low levels of efficacy, potentially because the affinity for TGF-beta was not great enough to dampen its ability to signal and activate the associated cellular processes.
Commercial Applications & Advantages:
- This TGF-beta trap approach may be useful for treating and/or ameliorating cancer, especially at the metastatic stages
- One of the inhibitors shows a 1000 fold improvement of TGF-beta inhibition in preliminary biochemical and cell-based studies other monoclonal antibodies in development.
- The specificity and higher affinity of theses TGF-beta receptor fusion proteins overcome the deficiencies of existing TGF-beta inhibitors; they are much more specific than the kinase inhibitors and they have several advantages over other monoclonal antibodies in development, including:
- Affinities that are 3 to 4 orders of magnitude greater in affinity; this may be important in enabling them to compete against the endogenous receptor complex (a heterotetramer that binds TGF-betas with picomolar affinity) for TGF-beta binding.
- Significantly smaller size, which may improve its ability to penetrate into tumors and the microenvironment
- Absence of Fc domains, which will prevent binding to endogenous Fc receptors, and thus prevent microlocalization that hinders tumor and tissue penentration.