Activatable interleukin-2 polypeptides and methods of use thereof
Inventors
Winston, William • Hicklin, Daniel • Bhaskar, Vinay • Evnin, Luke • Baeuerle, Patrick • SALMERON GARCIA, Jose Andres • Brodkin, Heather • Seidel-Dugan, Cynthia
Assignees
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Publication Number
US-11535658-B2
Publication Date
2022-12-27
Expiration Date
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.
Core Innovation
The invention concerns cytokines comprising an IL-2 polypeptide linked to an IL-2 blocking moiety and to a first half-life extension domain. The first half-life extension domain is polyethylene glycol, human serum albumin or a fragment that binds neonatal Fc receptor (FcRn), an immunoglobulin Fc, or an antigen-binding portion of an antibody that binds FcRn or human serum albumin.
The IL-2 blocking moiety includes 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. The IL-2 blocking moiety is operably linked to the first half-life extension domain via a first linker, and the IL-2 polypeptide is operably linked to the IL-2 blocking moiety via a second linker comprising a cleavable peptide.
This architecture configures IL-2 receptor activating behavior through the cleavable second linker and the IL-2 blocking moiety. The IL-2 blocking moiety inhibits activation of the IL-2 receptor alpha/beta/gamma by the IL-2 polypeptide, and the construct is described as an activatable, conditionally active cytokine fusion protein that restores IL-2 receptor activating activity after cleavage.
Claims Coverage
The consolidated claim coverage includes two independent claims directed to cytokine fusion constructs with a first half-life extension domain, an IL-2 polypeptide, and an IL-2 blocking moiety connected through a two-linker architecture including a cleavable peptide. The inventive features focus on the half-life extension domain format, the blocking moiety type, and the linker architecture with a cleavable peptide.
Two-linker cytokine architecture with a cleavable peptide in the second linker
A cytokine comprising a first half-life extension domain, an IL-2 polypeptide, and an IL-2 blocking moiety, 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.
Cytokine with PEG or Fc/HSA half-life extension and IL-2 binding blocking moiety
The cytokine wherein the first half-life extension domain is polyethylene glycol, human serum albumin or a fragment that binds neonatal Fc receptor (FcRn), an immunoglobulin Fc, or an antigen-binding portion of an antibody that binds FcRn or human serum albumin, and 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.
Cytokine with immunoglobulin Fc half-life extension and cognate receptor fragment blocking moiety
A cytokine comprising a first half-life extension domain that is an immunoglobulin Fc, an IL-2 polypeptide, and an IL-2 blocking moiety wherein the IL-2 blocking moiety comprises a fragment of a cognate receptor for the IL-2 polypeptide, with the IL-2 blocking moiety operably linked to the first half-life extension domain via a first linker and the IL-2 polypeptide operably linked to the IL-2 blocking moiety via a second linker comprising a cleavable peptide.
The independent claim set is centered on a cytokine fusion construct that includes a half-life extension domain, an IL-2 polypeptide, and an IL-2 blocking moiety, with a two-linker arrangement in which the IL-2 polypeptide is connected to the blocking moiety through a second linker comprising a cleavable peptide. The claims further distinguish embodiments by specifying the half-life extension domain and the IL-2 blocking moiety composition.
Stated Advantages
The uncleaved form has reduced IL-2 receptor activating activity and regains IL-2 receptor activating activity after cleavage associated with release of the blocking moiety.
Supports attenuated IL-2 receptor activating activity, including at least 10-fold reduced IL-2 receptor activating activity tied to cleavage conditions.
Supports reduced toxicity in vivo for cleavable versus non-cleavable variants.
Documented Applications
Therapeutic use for cancer and other immune-related diseases.
Evaluation of tumor xenograft efficacy in a xenograft tumor model.
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