We have harnessed this natural targeting ability of NRG by fusing the HBD of NRG to soluble HER4. This fusion protein retains high affinity heparin binding to heparin and to cells that express heparan sulfates resulting in a more potent NRG antagonist. In vivo, it is targeted to peripheral nerve segments where it blocks the activity of NRG as a Schwann cell survival factor. The fusion protein also efficiently blocks autocrine and paracrine signaling and reduces the proliferation of certain cancer cells. These findings demonstrate the utility of the HBD of NRG in biopharmaceutical targeting and provide a new way to block HER signaling in cancer cells.
BACKGROUND:
A major limitation in biopharmaceutical development is selectively targeting drugs to diseased tissues. Growth factors and viruses have solved this problem by targeting tissue-specific cell-surface heparan sulfates. Neuregulin (NRG), a growth factor important in both nervous system development and cancer, has a unique heparin-binding domain (HBD) that targets to cell surfaces expressing its HER2/3/4 receptors.
BENFITS:
· Reducing toxicity
· Improving efficacy
· Improving stability
· Reducing dosing frequency
· Targets specific cell surfaces through heparan sulfate binding
· Can be linked to a wide variety of biopharmaceuticals
PATENTS:
Patents applied for in USA, Australia, Canada, Europe, and Japan
PUBLICATIONS:
Targeting Human Epidermal Growth Factor Receptor Signaling with the Neuregulin’s Heparin-binding Domain