Method of treating graft versus host disease with an interleukin-2 mutein
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-10654905-B2
Publication Date
2020-05-19
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
Novel human interleukin-2 (IL-2) muteins or variants thereof are provided, characterized by increased binding capacity for IL-2Rβ receptor and decreased binding capacity for IL-2Rγc receptor compared to wild-type IL-2. These IL-2 muteins function as partial agonists and antagonists to modulate IL-2 and IL-15 functions. Pharmaceutical compositions including these muteins and methods of treatment using these compositions are also described.
Interleukin-2 (IL-2) is a cytokine critical for immune response, mediating T cell proliferation, B cell growth, and natural killer cell activation. IL-2 signals through a receptor complex including IL-2Rα, IL-2Rβ, and IL-2Rγc subunits. While IL-2 stimulates immune activation, it can also mediate autoimmunity and transplant rejection. There is a therapeutic need for IL-2 muteins that can block specific IL-2 and IL-15 functions by altering receptor binding, particularly to reduce untoward immune responses.
The invention addresses this need by creating IL-2 muteins with enhanced IL-2Rβ binding but diminished IL-2Rγc binding to disrupt IL-2Rβ-γc heterodimerization and signaling. This results in partial agonists and antagonists that functionally block endogenous cytokine activity without inducing signaling. Such molecules can serve as a “receptor signaling clamp” to inhibit pathological IL-2 and IL-15 mediated activities, for example in graft versus host disease and adult T cell leukemia treatment.
Claims Coverage
The patent contains one independent claim focused on a method for treating graft versus host disease (GVHD) using a specifically mutated IL-2 mutein pharmaceutical composition.
IL-2 mutein with specified amino acid substitutions for therapeutic use
A method of treating a subject having GVHD by administering a pharmaceutical composition comprising an IL-2 mutein with amino acid substitutions L18R, Q22E, Q126T, and S130R, exhibiting increased IL-2Rβ binding affinity and decreased IL-2Rγc binding affinity relative to wild-type IL-2.
Additional mutations enhancing IL-2Rβ binding
The IL-2 mutein may further include one or more amino acid substitutions selected from Q74N, Q74H, Q74S, L80F, L80V, R81D, R81T, L85V, I86V, I89V, and I93V to increase IL-2Rβ receptor affinity.
IL-2 mutein fused to human Fc antibody fragment or other polypeptides
The IL-2 mutein may be linked to a human Fc antibody fragment, a heterologous polypeptide, or an albumin polypeptide to form fusion proteins for enhanced therapeutic properties.
The claims cover a method of treating GVHD with IL-2 muteins mutated to have reduced IL-2Rγc binding and enhanced IL-2Rβ binding, optionally fused to Fc or other polypeptides, establishing compositions and treatment methods leveraging these mutated IL-2 variants.
Stated Advantages
IL-2 muteins function as IL-2 partial agonists and antagonists capable of selectively inhibiting IL-2 and IL-15 signaling pathways.
These muteins provide enhanced binding to IL-2Rβ allowing them to block endogenous cytokine signaling effectively.
Use of IL-2 muteins reduces adverse effects, such as pulmonary edema, observed with wild-type IL-2 treatments.
IL-2 muteins demonstrate enhanced anti-tumor responses relative to wild-type IL-2.
The muteins exhibit promise in treating graft versus host disease by prolonging survival in murine models.
Documented Applications
Treatment of graft versus host disease (GVHD) using IL-2 muteins with reduced IL-2Rγc binding and increased IL-2Rβ affinity.
Treatment of adult T-cell leukemia (ATL) with IL-2 muteins that antagonize IL-2 and IL-15 signaling.
Use of IL-2 muteins as IL-2 partial agonists and antagonists in conditions requiring reduction or inhibition of IL-2 and IL-15 functions.
Potential enhancement of natural killer cell-mediated cytotoxicity and improvement of anti-tumor immune responses.
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