Interleukin-2 agents and uses thereof
Inventors
Carlson, Scott Moore • Babcock, Gregory • Shriver, Zachary • Ramakrishnan, Boopathy
Assignees
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Publication Number
US-12297249-B2
Publication Date
2025-05-13
Expiration Date
Abstract
IL-2 agents that comprise IL-2 variants are disclosed as well as methods, compositions, and uses thereof. The IL-2 agents described herein can be used to treat and/or prevent various disorders and conditions.
Core Innovation
The invention relates to interleukin-2 (IL-2) agents, including an IL-2 variant and an Fc region, engineered to stabilize IL-2 and modulate IL-2 receptor binding. The IL-2 variant is defined by amino-acid substitutions and sequence identity to a reference sequence, and the IL-2 agent further includes Fc fusion or conjugate formats.
A central design aspect is reducing affinity for the IL-2Rβ/γ signaling complex (CD122/CD132), with an optional approach to reduce or preserve binding to CD25 (IL-2Rα). The stated technical effect is selective activation or expansion of regulatory T cells (Tregs), involving IL-2 signaling with diminished impact on other immune cells such as T helper cells and natural killer (NK) cells, including signaling readouts associated with pSTAT5.
The disclosure also associates the engineered IL-2 agents with improved stability, reduced aggregation, reduced incorrect disulfide pairing, and extended half-life or reduced clearance. Representative molecular components include IL-2 variants, Fc moieties, and conjugate or fusion constructs with defined linkers and geometries, including Fc allotypes and specific Fc substitutions.
Claims Coverage
The independent claim covers an IL-2 conjugate defined by an IL-2 variant sequence constraint and three specific amino-acid substitutions, together with an Fc region. The claim set includes dependent refinements that specify particular IL-2 and Fc sequences, Fc substitutions, fusion topology, and dimer formation, including homodimer.
IL-2 conjugate with stabilized IL-2 variant and Fc region
An IL-2 conjugate comprising an IL-2 variant and an Fc region, wherein the IL-2 variant comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, and Q74P.
IL-2 variant defined by SEQ ID NO: 5
The IL-2 conjugate wherein the IL-2 variant comprises an amino acid sequence set forth in SEQ ID NO: 5.
IgG1 Fc region with EU-numbered N297G substitution
The IL-2 conjugate wherein the Fc region of IgG1 comprises an amino acid substitution N297G according to EU numbering.
Fc region defined by SEQ ID NO: 1003
The IL-2 conjugate wherein the Fc region comprises an amino acid sequence set forth in SEQ ID NO: 1003.
Fc fused to the C-terminus of the IL-2 variant
The IL-2 conjugate wherein the Fc region is fused to the C-terminus of the IL-2 variant.
Homodimeric dimer formation
The IL-2 conjugate wherein the dimer is a homodimer.
Across the independent and dependent claim coverage provided, the invention centers on IL-2 conjugates combining an Fc region with a stabilized IL-2 variant defined by at least 95% identity to a reference sequence and specific substitutions H16L, V69A, and Q74P, further narrowed by particular IL-2/Fc sequence identities, Fc substitutions including EU-numbered N297G, fusion topology, and dimer form.
Stated Advantages
Improved stability.
Reduced incorrect disulfide pairing.
Reduced aggregation.
Extended half-life or reduced clearance.
Reduced effector-cell and NK activation.
Reduced CD122/CD132 binding.
Reduced CD25 affinity.
Selective activation or expansion of regulatory T cells (Tregs).
Increased therapeutic window.
Documented Applications
Therapeutic targeting using Treg selectivity for autoimmune disorders.
In vivo modulation of circulating immune-cell populations (NK cells, cytotoxic T cells, helper T cells, total T cells) in cynomolgus monkeys.
Assessment of disease impact in a murine lupus nephritis-like systemic lupus erythematosus model using proteinuria scores, individual mouse plots, and glomerular lesion quantification.
Treatment of immune-mediated disorders, including autoimmune diseases such as lupus nephritis and autoimmune hepatitis.
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