Superagonists, partial agonists and antagonists of interleukin-2
Inventors
GARCIA, Christopher K. • MITRA, Suman • Leonard, Warren J. • RING, Aaron M.
Assignees
National Institutes of Health NIH • Leland Stanford Junior University
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Publication Number
US-11384131-B2
Publication Date
2022-07-12
Expiration Date
2035-04-24
Abstract
Novel human interleukin-2 (IL-2) muteins or variants thereof are provided. In particular, provided are IL-2 muteins that have an increased binding capacity for IL-2Rβ receptor and a decreased binding capacity for IL-2Rγc receptor, as compared to wild-type IL-2. Such IL-2 muteins are useful, for example, as IL-2 partial agonist and antagonists in applications where reduction or inhibition of one or more IL-2 and/or IL-15 functions is useful (e.g., in the treatment of graft versus host disease (GVHD) and adult T cell leukemia). Also provided are nucleic acids encoding such IL-2 muteins, methods of making such IL-2 muteins, pharmaceutical compositions that include such IL-2 muteins and methods of treatment using such pharmaceutical compositions.
Core Innovation
This invention provides novel human interleukin-2 (IL-2) muteins or variants that have an increased binding capacity for the IL-2Rβ receptor and a decreased binding capacity for the IL-2Rγc receptor compared to wild-type IL-2. These muteins function as IL-2 partial agonists and antagonists, useful in applications where reduction or inhibition of one or more IL-2 and/or IL-15 functions is desirable. Also provided are nucleic acids encoding these IL-2 muteins, methods of making them, pharmaceutical compositions including such muteins, and methods of treatment using such compositions.
The problem addressed arises from the pleiotropic and complex actions of IL-2 in immune regulation, where its stimulatory effects, although useful in treating cancer and chronic viral infections, can also mediate autoimmunity and transplant rejection. Existing monoclonal antibodies targeting IL-2Rα or IL-2Rβ do not effectively block IL-2 signaling via intermediate affinity receptors or IL-15 signaling and therefore new IL-2 muteins capable of blocking one or more IL-2 and/or IL-15 functions are needed. The provided IL-2 muteins aim to function as mechanism-based IL-2 partial agonists and antagonists by attenuating IL-2Rβ-γc heterodimerization and signaling upon binding to IL-2Rβ-positive cells, thereby reducing or inhibiting endogenous cytokine signaling.
The invention describes IL-2 muteins with mutations that enhance IL-2Rβ binding while decreasing IL-2Rγc binding to create a dominant-negative scaffold or "receptor signaling clamp." This receptor targeting strategy aims to generate non-signaling or weakly signaling IL-2 variants that block endogenous IL-2 and IL-15 activity, functioning as partial agonists or antagonists. Such IL-2 muteins have potential therapeutic applications, including for the treatment of graft versus host disease (GVHD) and adult T cell leukemia, where suppression of specific IL-2/IL-15 dependent functions is beneficial.
Claims Coverage
The patent contains one independent claim covering a therapeutic method using a specified IL-2 mutein with defined amino acid substitutions and altered receptor binding affinities.
Method of treating cancer with an IL-2 mutein having specific amino acid substitutions and altered receptor binding affinities
A method of treating a subject having cancer (leukemia or breast cancer) by administering a therapeutically effective amount of a pharmaceutical composition comprising an IL-2 mutein with amino acid substitutions L18R, Q22E, Q126T, and S130R as numbered in wild-type human IL-2, wherein the mutein has increased binding affinity for IL-2Rβ and decreased binding affinity for IL-2Rγc receptor compared to wild-type IL-2.
Inclusion of additional amino acid substitutions to increase IL-2Rβ binding affinity in the IL-2 mutein
The IL-2 mutein further comprises one or more amino acid substitutions selected from Q74N, Q74H, Q74S, L80F, L80V, R81D, R81T, L85V, I86V, I89V, and I93V to further increase binding affinity to IL-2Rβ.
Linking of the IL-2 mutein to human Fc antibody fragment or heterologous polypeptides
The IL-2 mutein can be linked to a human Fc antibody fragment, a heterologous polypeptide, or an albumin polypeptide to form a fusion protein to potentially alter pharmacokinetic properties.
Treatment of IL-2 and/or IL-15 mediated leukemias using the IL-2 mutein
Utilizing the IL-2 mutein for treatment of IL-2 and/or IL-15 mediated leukemias, specifically including adult T-cell leukemia (ATL), chronic or smoldering ATL, and chronic myelogenous leukemia (CML).
The claims focus on therapeutic methods using specific IL-2 muteins with defined receptor binding alterations and amino acid substitutions, applicable to cancer treatment including leukemias and breast cancer, with potential fusion constructs for improved delivery and efficacy.
Stated Advantages
The IL-2 muteins can act as IL-2 partial agonists and antagonists that block endogenous IL-2 and IL-15 functions.
The IL-2 muteins have increased binding affinity for IL-2Rβ while decreased affinity for IL-2Rγc, allowing for selective modulation of receptor signaling.
The muteins reduce adverse effects associated with wild-type IL-2 therapy, such as vascular leak syndrome and acute pulmonary edema.
The IL-2 muteins demonstrate enhanced stimulation of memory phenotype CD8+ T cells with reduced stimulation of regulatory T cells (Tregs).
The muteins exhibit enhanced anti-tumor responses in vivo relative to wild-type IL-2.
Mutant IL-2-Fc fusion proteins have improved pharmacokinetics and increased therapeutic potency.
Documented Applications
Treatment of graft versus host disease (GVHD) by administering IL-2 muteins that suppress IL-2 and IL-15 signaling.
Treatment of adult T-cell leukemia (ATL), including chronic and smoldering forms, using IL-2 muteins as antagonists.
Treatment of cancers, specifically leukemia and breast cancer, using IL-2 muteins with altered receptor binding affinities.
Use of IL-2 mutein fusion proteins for therapeutic applications requiring modulation of immune responses.
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