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-10150802-B2
Publication Date
2018-12-11
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-2RP receptor and a decreased binding capacity for IL-2RΥc 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
Novel human interleukin-2 (IL-2) muteins or variants are provided, particularly those with increased binding capacity for the IL-2Rβ receptor and decreased binding capacity for the IL-2Rγc receptor compared to wild-type IL-2. These IL-2 muteins are useful as IL-2 partial agonists and antagonists in applications where reduction or inhibition of one or more IL-2 and/or IL-15 functions is desirable, such as in treating graft versus host disease (GVHD) and adult T cell leukemia.
Interleukin-2 is a pluripotent cytokine crucial for normal immune responses, promoting proliferation and expansion of lymphocytes and activating various immune cells. IL-2 signals via three receptors: IL-2Rα, IL-2Rβ, and IL-2Rγc. While existing monoclonal antibodies target IL-2Rα and show efficacy in some conditions, they do not effectively block signaling through intermediate affinity IL-2Rβ-γc receptors and cannot block IL-15 signaling. Hence, there is a need for novel IL-2 muteins that can block one or more functions of IL-2 and/or IL-15.
The invention builds on prior development of IL-2 superagonists with enhanced binding affinity for IL-2Rβ, hypothesizing that directed mutation of these superagonists to reduce binding to IL-2Rγc would attenuate IL-2Rβ-γc heterodimerization. This creates a receptor signaling clamp acting as partial agonists or antagonists that block endogenous cytokine signaling while exerting little or no agonist effect. Such mechanism-based IL-2 muteins could selectively alter IL-2 dependent immune functions, providing new therapeutic modalities.
Claims Coverage
The patent discloses two main independent claims covering IL-2 muteins with altered receptor binding affinities and compositions comprising these muteins.
IL-2 muteins with altered receptor binding affinities
IL-2 muteins having increased binding affinity for IL-2Rβ and decreased binding affinity for IL-2Rγc compared to wild-type human IL-2, comprising specific amino acid substitutions at positions L18R, Q22E, Q126T, and S130R.
Additional amino acid substitutions that increase IL-2Rβ binding affinity
IL-2 muteins further comprising one or more amino acid substitutions selected from Q74N, Q74H, Q74S, L80F, L8V, R81D, R81T, L85V, I86V, I89V, and I93V to further enhance IL-2Rβ binding affinity.
IL-2 mutein fusion proteins
IL-2 mutein fusion proteins comprising the above IL-2 muteins linked to a human Fc antibody fragment, a heterologous polypeptide, or an albumin polypeptide to enhance therapeutic properties.
Functional antagonist activities of the IL-2 muteins
The IL-2 muteins exhibit decreased capability to stimulate STAT5 phosphorylation and pERK1/ERK2 signaling in IL-2Rβ+ cells, act as antagonists of IL-2 and/or IL-15, and inhibit IL-2/IL-15 induced proliferation and differentiation events, including Th1, Th9, Treg differentiation and natural killer cell activation.
The claims cover IL-2 muteins with specified substitutions that enhance IL-2Rβ binding and reduce IL-2Rγc binding, leading to partial agonist or antagonist functional properties, including fusion proteins with improved therapeutic uses. The inventive features focus on the specific mutations and their consequent receptor binding and functional effects.
Stated Advantages
IL-2 muteins provide a mechanism-based approach to selectively inhibit IL-2 and IL-15 signaling by attenuating IL-2Rβ-γc heterodimerization.
The IL-2 muteins can function as partial agonists or non-signaling antagonists, enabling modulation of immune responses with controlled signaling efficacy.
Therapeutic use of IL-2 muteins can reduce harmful immune activation, such as transplant rejection or autoimmunity, with less toxicity than wild-type IL-2.
IL-2 muteins fused to Fc fragments or albumin can have extended circulating half-life, improving therapeutic profiles.
The IL-2 muteins can inhibit pathological proliferation in diseases like graft versus host disease and adult T cell leukemia more effectively than existing monoclonal antibodies.
Documented Applications
Treatment of graft versus host disease (GVHD) by administering IL-2 muteins that act as antagonists of IL-2 and IL-15.
Treatment of adult T-cell leukemia (ATL), particularly chronic and smoldering forms, through IL-2 antagonistic IL-2 muteins.
Use as immunomodulatory agents to reduce or inhibit one or more functions of IL-2 and/or IL-15 in immune-related conditions.
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