Use of glucocorticoid receptor modulators to potentiate checkpoint inhibitors
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Publication Number
US-12171760-B2
Publication Date
2024-12-24
Expiration Date
Abstract
This invention provides a method that combines a checkpoint inhibitor and a glucocorticoid receptor modulator to treat cancer, e.g., a checkpoint inhibitor sensitive cancer.
Core Innovation
The invention provides a method for reducing tumor load in a patient hosting a tumor of a glucocorticoid receptor (GR+) cancer by administering a selective glucocorticoid receptor modulator (SGRM) that potentiates an antibody checkpoint inhibitor. The potentiation is effective to provide superior tumor load reduction compared with tumor load reduction provided by the antibody checkpoint inhibitor alone, and is also effective to reduce tumor load of the GR+ cancer.
The SGRM is administered as CORT 125134, also identified as (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone. The method includes treatment with an antibody checkpoint inhibitor effective against PD-1 selected from lambrolizumab, nivolumab, AMP-224, and pidilizumab and an antibody checkpoint inhibitor effective against CTLA-4 selected from ipilimumab and tremelimumab.
In the disclosed context, SGRMs are identified and qualified through GR binding assays and functional assays using GRE-dependent genes and cell-based signaling, reporter, and repression assays. Documented examples include CORT125134 and CORT125281, and tumor models demonstrating tumor reduction when combined with anti-PD-1 or anti-CTLA-4 checkpoint inhibitors, including examples referencing breast cancer.
Claims Coverage
The claims cover a GR+ cancer patient method with four inventive features centered on CORT 125134, intermittent PD-1 and/or CTLA-4 antibody checkpoint inhibitor treatment, and at least 10% greater tumor load reduction than antibody checkpoint inhibitor alone.
Potentiating checkpoint inhibitor activity for gr+ tumor load reduction
A method effective to potentiate the activity of an antibody checkpoint inhibitor to provide superior tumor load reduction compared to the antibody checkpoint inhibitor alone, and to reduce tumor load of said GR+ cancer.
Administering a selective glucocorticoid receptor modulator (SGRM) having a specified structure
Administering a therapeutic amount of the selective glucocorticoid receptor modulator (SGRM) CORT 125134, also identified as (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the structure as shown.
Intermittent checkpoint inhibitor treatment with specified pd-1 and ctla-4 antibodies
Administering the SGRM when the patient is receiving treatment comprising intermittent administration of an antibody checkpoint inhibitor effective against PD-1 selected from lambrolizumab, nivolumab, AMP-224, and pidilizumab, and an antibody checkpoint inhibitor effective against CTLA-4 selected from ipilimumab and tremelimumab.
Performance criteria for potentiation and tumor reduction
Wherein said potentiation of said antibody activity is effective to provide at least 10% greater tumor load reduction in the patient as compared to the tumor load reduction provided by the antibody checkpoint inhibitor alone and to reduce the tumor load of said GR+ cancer.
The claims center on combining CORT 125134 with intermittent PD-1 and/or CTLA-4 antibody checkpoint inhibitor treatment to achieve at least 10% greater tumor load reduction in GR+ cancers than checkpoint inhibitor alone.
Stated Advantages
Provides superior tumor load reduction compared to tumor load reduction provided by the antibody checkpoint inhibitor alone.
Potentiates the activity of an antibody checkpoint inhibitor.
Provides at least 10% greater tumor load reduction compared to tumor load reduction provided by the antibody checkpoint inhibitor alone.
Reduces tumor load of the GR+ cancer in the patient.
Documented Applications
Reducing tumor load in a patient hosting a tumor of a glucocorticoid receptor (GR+) cancer by potentiating antibody checkpoint inhibitor activity.
Use in combination with antibody checkpoint inhibitors effective against PD-1 (lambrolizumab, nivolumab, AMP-224, pidilizumab) and/or effective against CTLA-4 (ipilimumab, tremelimumab), as described in tumor model examples including anti-PD-1/anti-CTLA-4 combinations.
Breast cancer patient example is described.
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