Immunotherapeutic tumor treatment method
Inventors
Kivimae, Saul • Hennessy, Marlene • Anand, Neel K. • Cai, Haiying • Deng, Bo-Liang • Ren, Zhongxu • Joshi, Bhalchandra V.
Assignees
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Publication Number
US-12054553-B2
Publication Date
2024-08-06
Expiration Date
Abstract
Provided is a method of administering to a patient having cancer: (a) a 4-1BB agonist; (b) an IL-2Rβ-activating amount of a long-acting, IL-2Rβ-selective agonist; and/or (c) a toll-like receptor agonist, as well as related compositions, kits and compositions.
Core Innovation
The invention relates to cancer immunotherapy regimens that administer, to a subject having a cancer, a 4-1BB agonist together with a long acting IL-2Rβ-preferential agonist and a toll-like receptor (TLR) agonist. The IL-2Rβ component is described as an IL-2Rβ-activating amount of an IL-2Rβ-preferential agonist of a formula in which n ranges from 3 to 4,000. The TLR component is a TLR agonist selected from compounds in which each n for Compounds 5 and 6 is independently an integer from 40 to 350, including pharmaceutically acceptable salt forms.
The disclosed combination therapy is positioned within a tri-modal cancer immunotherapy context, including a 4-1BB agonist, an IL-2Rβ-biased agonist, and a TLR agonist. The document characterizes IL-2Rβ bias as avoiding IL-2-driven Treg expansion, while 4-1BB costimulation enhances T-cell effector activity. The TLR7/8 agonists are described as creating a tumor-suppressive innate immune microenvironment.
The document further reports mechanistic and experimental findings in mouse models, including strong systemic and abscopal responses. It links IL-2Rβ-biased and TLR7/8 treatment to unexpected CD11c+ CD8 T-cell phenotypes, with involvement of dendritic cells, macrophages, neutrophils, and monocytes, as well as suppression of T regulatory cells (Tregs).
The disclosed regimen includes named agents and polymer-conjugated TLR agonist examples, including urelumab and utomilumab for 4-1BB agonists and PEG-aldesleukin releasably covalently attached to PEG for the IL-2Rβ-biased agonist. For the TLR7/8 agonist, it includes resiquimod and imiquimod polymer conjugates, including multi-armed polymer-conjugated forms such as 4-arm-PEG20k-CM-glycine-N-R848.
Claims Coverage
The independent claim covers a combination administration method using three inventive drug classes/features: a 4-1BB agonist, a long acting IL-2Rβ-preferential agonist of a specified formula defined by n (3 to 4,000) at an IL-2Rβ-activating amount, and a TLR agonist selected from compounds defined by n (40 to 350 for Compounds 5 and 6).
Combination administration with 4-1BB agonist, long acting IL-2Rβ-preferential agonist, and TLR agonist
Administering to a subject having a cancer a 4-1BB agonist, administering an IL-2Rβ-activating amount of a long acting IL-2Rβ-preferential agonist of a formula (n ranges from 3 to 4,000) or a pharmaceutically acceptable salt, and administering a TLR agonist selected from compounds or pharmaceutically acceptable salt forms (each n for Compounds 5 and 6 is independently an integer from 40 to 350).
Across the independent claim, the inventive concept is the combined administration of a 4-1BB agonist with a long acting IL-2Rβ-preferential agonist (defined by the n range and an IL-2Rβ-activating amount) and a TLR agonist (selected from compounds defined by an n range), for a subject having cancer.
Stated Advantages
Avoidance of IL-2-driven Treg expansion (via IL-2Rβ bias).
Enhancement of T-cell effector activity (via 4-1BB costimulation).
Creation of a tumor-suppressive innate immune microenvironment (via TLR7/8 agonists).
Strong systemic and abscopal responses (described in mouse models).
Induction of unexpected CD11c+ CD8 T-cell phenotypes.
Suppression of T regulatory cells (Tregs).
Prolonged tumor retention with local intratumoral administration.
Enhanced tumor antigen presentation and CD8 T-cell priming.
Minimal systemic toxicity.
Effective to produce an abscopal effect on the cancer.
Documented Applications
Cancer immunotherapy using a tri-modal combination including a 4-1BB agonist, a long-acting IL-2Rβ-preferential (IL-2Rβ-biased) agonist, and a TLR agonist.
Local intratumoral administration of PEG-conjugated TLR7/8 agonists (resiquimod/imiquimod conjugates) to support tumor retention and immune priming.
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