Interleukin-2 agents and uses thereof
Inventors
Carlson, Scott Moore • Babcock, Gregory • Shriver, Zachary • Ramakrishnan, Boopathy
Assignees
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Publication Number
US-12084484-B2
Publication Date
2024-09-10
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 and IL-2 variants comprising amino acid sequences having at least 95% sequence identity to specified SEQ ID NOs and defined amino acid substitutions. The described substitution sets include H16L, H16N, or I92S together with V69A and Q74P, and in some embodiments C125S and T3A, with additional optional CD25-affinity-reducing mutations. The variants are presented as IL-2 agents/variants and as a platform to stabilize IL-2 and modulate IL-2 receptor binding properties.
The IL-2 variants are designed to reduce binding or affinity for IL-2 receptor subunits CD122 and CD132 relative to CD25 and to selectively activate IL-2 signaling in regulatory T cells (Tregs). The described outcomes include expansion of Tregs, including CD3+FoxP3+ T cells, with minimal or reduced effects on effector T cells, helper T cells, and NK cells. The disclosure also refers to altered IL-2 receptor binding, signaling potency including pSTAT5, and signaling selectivity ratios comparing Treg versus helper T cell and NK cell responses.
The invention further includes nucleic acids encoding the IL-2 variants, vectors and host cells for expression of the IL-2 agents/variants, and IL-2 fusion, complex, conjugate, and Fc region formats with linkers. The therapeutic methods administer IL-2 agents/variants to treat disorders, and the documented embodiments include lupus nephritis, autoimmune hepatitis, and nephrotic syndrome. The disclosure also mentions broad measurement contexts including stability, aggregation, half-life, turnover, clearance, and binding affinities.
Claims Coverage
The independent claims cover IL-2 variants defined by at least 95% sequence identity to specified SEQ ID NOs together with defined amino-acid substitution sets. Across the independent claims, three inventive features are most prominent: sequence identity constraints, substitution combinations centered on H16L/H16N/I92S with V69A and Q74P, and an additional C125S substitution in one SEQ ID NO:1031-based variant. Dependent claims further include selective Treg stimulation and pharmaceutical composition and kit formats.
Interleukin-2 variant defined by SEQ ID NO:1031 identity and substitution set
An interleukin-2 (IL-2) variant comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO:1031 and an amino acid substitution H16L, H16N, or I92S, and amino acid substitutions V69A, Q74P, and C125S.
Interleukin-2 variant defined by SEQ ID NO:1 identity and substitution set
An interleukin-2 (IL-2) variant comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO:1 and an amino acid substitution H16L, H16N, or I92S, and amino acid substitutions V69A and Q74P.
Selective stimulation of regulatory T cells (Tregs)
An IL-2 variant that selectively stimulates regulatory T cells (Tregs).
Pharmaceutical composition with an IL-2 variant and pharmaceutically acceptable carrier
A pharmaceutical composition comprising an IL-2 variant together with a pharmaceutically acceptable carrier.
Kit including the IL-2 variant
A kit that includes the IL-2 variant.
Overall, the claim coverage is anchored in IL-2 variants with high sequence identity to specified SEQ ID NOs and defined substitution sets, including H16L/H16N/I92S together with V69A and Q74P, and in one independent claim also C125S. Dependent claims additionally capture selective Treg stimulation, pharmaceutical compositions, and kits.
Stated Advantages
Selective stimulation of regulatory T cells (Tregs) with minimal effects on effector T cells and NK cells.
Expansion of Tregs, including CD3+FoxP3+ T cells.
Selectively activates IL-2 signaling in regulatory T cells (Tregs).
Reduces off-target activation of helper T cells and NK cells.
Reduced kidney damage in a murine lupus nephritis model.
Preferential activation and expansion of regulatory T cells (Tregs) while minimizing effects on NK cells and T effector subsets.
Reduced proteinuria and glomerular lesions versus PBS in a murine lupus nephritis model.
Reduced CD122/CD132 binding with enhanced Treg selectivity.
Selective or concomitant lack of CD25-high effects.
Reduced CD25 binding and improved agent lifetime.
Reduced T-effector/NK expansion.
Improved stability and reduced incorrect disulfide pairing (at C125S).
Extended half-life.
Improved Fc-mediated half-life for Fc-containing fusions.
Improved stability.
Documented Applications
Therapeutic treatment of lupus nephritis using IL-2 agents/variants.
Therapeutic treatment of autoimmune hepatitis using IL-2 agents/variants.
Therapeutic treatment of nephrotic syndrome using IL-2 agents/variants.
Treating autoimmune and other immune-related disorders, including autoimmune diseases such as lupus nephritis, autoimmune hepatitis, nephrotic syndrome, and cancer.
Immune-cell response context in cynomolgus monkeys, with fold-change effects on NK, cytotoxic T, helper T, and total T cells after weekly administration of an IL-2-Fc fusion.
Treatment of murine lupus nephritis, where an exemplary IL-2-Fc reduces proteinuria and glomerular lesions versus PBS.
Immune modulation, including utility described for autoimmune disease such as lupus nephritis.
Use of IL-2 complexes/conjugates and IL-2/anti-IL-2 immune complexes for immune modulation.
Pharmaceutical composition use of the IL-2 variant with a pharmaceutically acceptable carrier.
Kit formats that include the IL-2 variant.
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