IL-13/IL-4 superkines: immune cell targeting constructs and methods of use thereof
Inventors
Garcia, Kenan Christopher • Gonzalez, Ignacio Moraga • Merchant, Fahar
Assignees
Medicenna Therapeutics Inc • Leland Stanford Junior University
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Publication Number
US-12590133-B2
Publication Date
2026-03-31
Expiration Date
Abstract
Methods and compositions are provided for enhancing anti-tumor effector immune cells with a targeting construct comprising a human IL-13 superkine and/or a human IL-4 superkine. Cytokine or additional co-stimulatory sequences may also be included to enhance the tumoricidal effects of the cells.
Core Innovation
The disclosure describes immune cell targeting constructs that target a tumor and/or tumor microenvironment and/or tumor antigens. The constructs include an IL-13 superkine engineered to increase affinity for interleukin 13 receptor β2 (IL-13Rβ2) relative to native human IL-13 protein and to decrease affinity for interleukin 13 receptor α1 (IL-13Rα1) relative to native human IL-13 protein.
The IL-13 superkine comprises at least one amino acid change relative to wild-type IL-13 at one or more positions selected from L10, R11, E12, I14, V18, R65, R86, D87, T88, K89, L101, K104, K105, F107, and R108. The constructs are combined as compositions with an IL-2 or an IL-2 mutein.
In certain embodiments, the immune cell targeting construct is a CAR in which the IL-13 superkine is fused to a transmembrane domain and linked to an intracellular signaling region. The intracellular signaling region comprises one or more of a CD3ζ signaling domain, a CD28 signaling domain, a CD137 signaling domain, an OX-40 signaling domain, an ICOS signaling domain, and a DAP10 signaling domain.
Claims Coverage
The independent claims cover immune cell targeting constructs that use an engineered IL-13 superkine with altered binding to IL-13Rβ2 and IL-13Rα1, combined with an IL-2 or an IL-2 mutein. The coverage includes five inventive features centered on the receptor-binding-altered IL-13 superkine, tumor targeting, CAR fusion format, intracellular signaling domain selection, and specified substitution sets.
Immune cell targeting construct with engineered IL-13 superkine binding selectivity for IL-13 receptors
An immune cell targeting construct comprising an IL-13 superkine engineered to have increased affinity for interleukin 13 receptor β2 (IL-13Rβ2) relative to native human IL-13 protein and decreased affinity for interleukin 13 receptor α1 (IL-13Rα1) relative to native human IL-13 protein, with at least one amino acid change relative to wild-type IL-13 at one or more of positions L10, R11, E12, I14, V18, R65, R86, D87, T88, K89, L101, K104, K105, F107, and R108, wherein the immune cell targeting construct targets a tumor and/or tumor microenvironment and/or tumor antigens.
Composition comprising an immune cell targeting construct with an IL-2 or IL-2 mutein
A composition comprising an immune cell targeting construct and an IL-2 or an IL-2 mutein.
CAR fused to IL-13 superkine with transmembrane and intracellular signaling linkage
The immune cell targeting construct comprises a CAR fused to the IL-13 superkine, with a transmembrane and intracellular signaling linkage.
Intracellular signaling region comprising selected signaling domains
The intracellular signaling region comprises one or more of a CD3ζ signaling domain, a CD28 signaling domain, a CD137 signaling domain, an OX-40 signaling domain, an ICOS signaling domain, and a DAP10 signaling domain.
Enumerated IL-13 superkine substitution sets
The IL-13 superkine includes one of several specified sets of amino acid substitutions at particular positions.
The claims focus on IL-13 superkine-based immune cell targeting constructs, CAR fusions, selected intracellular signaling domains, IL-2 or IL-2 mutein combinations, and specified IL-13 superkine substitution sets.
Stated Advantages
Extended circulating half-life through Fc-based pharmacokinetic extension.
Increased affinity for IL-13Rβ2 relative to native human IL-13 protein and decreased affinity for IL-13Rα1 relative to native human IL-13 protein.
Documented Applications
Targeting a tumor and/or tumor microenvironment and/or targeting tumor antigens.
Immune-cell targeting construct formats, including CAR, NK, and T-cell engager fusion constructs.
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