Proproteins activatable interferon alpha

摘要

The present disclosure provides for proprotein and activatable proprotein compositions. A proprotein contains a functional protein (i.e. a full length protein or functional fragment thereof) which is coupled to a peptide mask that inhibits the binding of the functional protein to its target or binding partner. An activatable proprotein contains a functional protein coupled to a peptide mask, and further coupled to an activatable linker, wherein in an non-activated state, the peptide mask inhibits binding of the functional protein to its target or binding partner and in an activated state the peptide mask does not inhibit binding of the functional protein to its target or binding partner. Proproteins can provide for reduced toxicity and adverse side effects that could otherwise result from binding of a functional protein at non-treatment sites if it were not inhibited from binding its binding partner. Proproteins can further provide improved biodistribution characteristics. Proproteins containing a peptide mask can display a longer in vivo or serum half-life than the corresponding functional protein not containing a peptide mask. The disclosure further provides methods of screening for, making, and using these proproteins.

主权项

1. A composition comprising an activatable proprotein comprising:
a functional interferon-alpha (IFN-α) protein or a functional fragment thereof, a peptide mask that inhibits binding of the IFN-α functional protein to its binding partner, wherein the binding partner is a receptor for the IFN-α protein, and wherein the peptide mask comprises the amino acid sequence of SEQ ID NO: 13, 14 or 15, a cleavable linker, wherein the cleavable linker comprises a substrate for a protease, and wherein the protease is HCV-NS3/4 or matriptase, such that: (i) the peptide mask of the activatable proprotein in an uncleaved state inhibits binding of the IFN-α functional protein or functional fragment thereof to the receptor for the IFN-α protein and (ii) in a cleaved state, the peptide mask of the activatable proprotein in a cleaved state does not inhibit binding of the IFN-α functional protein or functional fragment thereof to the receptor for the IFN-α protein.