Activatable interleukin-2 polypeptides and methods of use thereof
AssigneeWerewolf Therapeutics, Inc.
InventorsWilliam Winston, Daniel Hicklin, Vinay Bhaskar, Luke Evnin, Patrick Baeuerle, Jose Andres Salmeron Garcia, Heather Brodkin, Cynthia Seidel-Dugan
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Abstract
The disclosure features fusion proteins that are conditionally active variants of IL-2. In one aspect, the full-length polypeptides of the invention have reduced or minimal cytokine-receptor activating activity even though they contain a functional cytokine polypeptide. Upon activation, e.g., by cleavage of a linker that joins a blocking moiety, e.g., a steric blocking polypeptide, in sequence to the active cytokine, the cytokine can bind its receptor and effect signaling.
Claims21
A cytokine comprising:
- a) a first half-life extension domain, wherein the first half-life extension domain is polyethylene glycol, human serum albumin or a fragment thereof that binds neonatal Fc receptor (FcRn), an immunoglobulin Fc, or an antigen-binding portion of an antibody that binds to FcRn or to human serum albumin;
- b) an IL-2 polypeptide;
- and
- c) an IL-2 blocking moiety, wherein the IL-2 blocking moiety comprises a ligand-binding domain or fragment of a cognate receptor for the IL-2 polypeptide or an antibody or antigen-binding fragment of an antibody that binds the IL-2 polypeptide;
- wherein the IL-2 blocking moiety is operably linked to the first half-life extension domain via a first linker, and wherein the IL-2 polypeptide is operably linked to the IL-2 blocking moiety via a second linker comprising a cleavable peptide.
A cytokine comprising:
- a) a first half-life extension domain, wherein the first half-life extension domain is an immunoglobulin Fc;
- b) an IL-2 polypeptide;
- and
- c) an IL-2 blocking moiety, wherein the IL-2 blocking moiety comprises a fragment of a cognate receptor for the IL-2 polypeptide;
- wherein the IL-2 blocking moiety is operably linked to the first half-life extension domain via a first linker, and wherein the IL-2 polypeptide is operably linked to the IL-2 blocking moiety via a second linker comprising a cleavable peptide.
Dependencies are inferred from the claim text.