Combination of a substance modulating tumor immune microenvironment and immunotherapy for the treatment of cancer
Inventors
LEE, GwangHee • RYOU, Jeonghyun • HUH, Jiwon • Taniguchi, Tadatsugu • Hangai, Sho • Yanai, Hideyuki
Assignees
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Publication Number
US-12329814-B2
Publication Date
2025-06-17
Expiration Date
Abstract
The present invention relates to a novel combination of (1) a substance that suppresses or inhibits the function of extracellular TCTP (translationally controlled tumor protein), especially released from tumor cells, and (2) a cancer immunotherapeutic agent for the treatment of cancer. Preferably, such a cancer immunotherapeutic agent is an immune checkpoint inhibitor. The substance that suppresses or inhibits the function of extracellular TCTP functions as an activator or enhancer of anti-tumor immune cells including T cells and natural killer (NK) cells and/or an antagonist of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), in the tumor immune microenvironment (TIME). The combination according to the present invention is useful for treating or preventing cancer. The combination according to the present invention is also useful for alleviating, reverting, or preventing immune suppression in the tumor immune microenvironment.
Core Innovation
The invention relates to a method for treating cancer in a patient in need thereof by administering a combination that includes a substance that suppresses or inhibits the function of extracellular translationally controlled tumor protein (TCTP) or its modified form, or a fragment or multimer thereof, together with a cancer immunotherapeutic agent. The substance is an antibody or antigen-binding fragment thereof that specifically binds to extracellular TCTP or its modified form, where the extracellular TCTP or its modified form has been released from tumor cells.
The cancer immunotherapeutic agent in the combination is an immune checkpoint inhibitor selected from an anti-PD-1 antibody and anti-CTLA-4 antibody. The disclosed concept is that extracellular TCTP is associated with immune suppression in the tumor immune microenvironment, and that suppressing or inhibiting extracellular TCTP modulates this immune suppression.
By suppressing or inhibiting extracellular TCTP, the combination is stated to activate or enhance the functions of T cells and and/or NK cells and to antagonize myeloid-derived suppressor cells (MDSCs). The mechanism is described in terms of reducing MDSCs and reducing CXCL1 expression, with an overall effect of improving anti-tumor immune activity and synergistic tumor suppression when combined with immune checkpoint inhibition.
The disclosed approach includes embodiments where the antibody or antigen-binding fragment comprises complementarity-determining regions (CDRs) selected from specified CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sets defined by SEQ ID NOs. Additional embodiments specify that the extracellular TCTP-suppressing substance can act by competitively inhibiting binding of an anti-TCTP antibody to TCTP.
Claims Coverage
The document provides one independent claim directed to a cancer treatment method using a combination therapy. The independent claim includes multiple inventive feature elements, including a defined extracellular TCTP-inhibiting antibody component and a specified immune checkpoint inhibitor component, with further limitation to specified CDR/SEQ ID sets.
Combination therapy with extracellular TCTP suppression and immune checkpoint inhibition
Administering a combination for treating cancer comprising (1) a substance that suppresses or inhibits the function of extracellular translationally controlled tumor protein (TCTP) or its modified form (or a fragment or multimer thereof) and (2) a cancer immunotherapeutic agent to a patient, where the immune checkpoint inhibitor is selected from an anti-PD-1 antibody and an anti-CTLA-4 antibody.
Extracellular TCTP inhibitor specifically binding released tumor-cell extracellular TCTP
Using, as the substance that suppresses or inhibits extracellular TCTP, an antibody or antigen-binding fragment thereof which specifically binds to extracellular TCTP or its modified form (or a fragment or multimer thereof), wherein the extracellular TCTP or its modified form (or fragment or multimer) has been released from tumor cells.
Defined CDR sets targeting extracellular TCTP or its modified form
Employing an antibody or antigen-binding fragment thereof that specifically binds extracellular TCTP or its modified form (or fragment or multimer thereof) and comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 selected from CDR sequence sets defined by SEQ ID NO: 1-6, 7-12, 13-18, or 19-24.
Across the independent claim, the core inventive coverage is directed to administering an immune checkpoint inhibitor (anti-PD-1 or anti-CTLA-4) together with an antibody-based substance that specifically suppresses or inhibits the function of extracellular TCTP released from tumor cells, where the antibody is defined by particular CDR/SEQ ID sets.
Stated Advantages
Activating or enhancing the functions of T cells and and/or NK cells.
Antagonizing MDSCs.
Reducing MDSCs and reducing CXCL1 expression.
Synergistic tumor suppression with immune checkpoint inhibition, including comparisons against anti-PD-L1.
Documented Applications
Treating cancer in a patient in need thereof by administering a combination comprising an extracellular TCTP-suppressing substance (specifically binding released extracellular TCTP) and an immune checkpoint inhibitor selected from anti-PD-1 antibody and anti-CTLA-4 antibody.
Treating cancer selected from colorectal cancer, melanoma, or fibrosarcoma using the method that administers the combination including extracellular TCTP suppression and an immune checkpoint inhibitor.
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