group of novel pan-TGF-beta inhibitor fusion proteins bind TGF-betas with
higher affinity than other compounds currently in preclinical and clinical
TGF-beta antagonist may be useful for treating and/or ameliorating cancer,
especially at the metastatic stages.
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.
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.
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.
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
Blockage of all receptor binding sites with a single inhibitor molecule
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
Status: PCT filed. Part of patent portfolio that
includes issued U.S. Patent 7,795,389.