Method of treating cancer using a combination of entinostat and an anti-CSF-1R antibody
Inventors
Assignees
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Publication Number
US-12168054-B2
Publication Date
2024-12-17
Expiration Date
Abstract
The present disclosure relates to a combination of an anti-CSF-1R antibody or anti-CSF-1 antibody or antigen binding fragment thereof or an inhibitor of CSF-1R activity and an HDAC inhibitor, e.g., entinostat, and methods of using the combination for administering to subjects in need thereof for the treatment of cancer.
Core Innovation
The patent describes treating cancer by administering a combination comprising entinostat and an anti-CSF-1R antibody or an antigen-binding fragment thereof. The anti-CSF-1R antibody or antigen-binding fragment includes a heavy chain variable domain with CDR-H1, CDR-H2, and CDR-H3 sequences given in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively, and a light chain variable domain with CDR-L1, CDR-L2, and CDR-L3 sequences given in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively.
In embodiments, the anti-CSF-1R antibody is further defined by specified full-length heavy and light chain sequences, including a heavy chain comprising the sequence given in SEQ ID NO:23 and a light chain comprising the sequence given in SEQ ID NO:15, and other embodiments that specify heavy chain sequence given in SEQ ID NO:27 and light chain sequence given in SEQ ID NO:19. Certain embodiments specify constraints on binding affinity to human CSF-1R measured by surface plasmon resonance, and describe cross-blocking behavior.
The described rationale targets CSF-1/CSF-1R-mediated immune suppression, including tumor-associated macrophages (TAMs) and T regulatory cells (Tregs), and references tumor-infiltrating lymphocytes (TIL) changes such as an increased CD8:Treg ratio and reduced intratumoral Tregs and TAMs. A cancer therapy example is described for CT26 colon cancer using entinostat with an anti-CSF-1R antibody (Ab535), with improved survival and tumor growth inhibition and corresponding immune profiling changes.
Claims Coverage
The document provides two independent claims covering two administering formats: (i) a combination of entinostat with an anti-CSF-1R antibody/antigen-binding fragment defined by specific CDR sequences, and (ii) a synergistic composition of entinostat with an anti-CSF-1R antibody/antigen-binding fragment defined by specified heavy/light sequences and CDR sequences, with additional claim scope limitations on cancer indications. Across the independent claims, the main inventive features are the defined entinostat plus anti-CSF-1R antibody combination/synergistic composition and the antibody CDR/sequence definitions; additional refinements include binding-affinity constraints and administration relationship and cancer-type scope.
Entinostat combination with an anti-CSF-1R antibody defined by CDR sequences
A method of treating cancer by administering to a patient a combination comprising entinostat and an anti-CSF-1R antibody or an antigen-binding fragment thereof, wherein the anti-CSF-1R antibody or the antigen-binding fragment thereof comprises a heavy chain whose variable domain comprises CDR-H1, CDR-H2, and CDR-H3 with sequences given in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively, and a light chain whose variable domain comprises CDR-L1, CDR-L2, and CDR-L3 with sequences given in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively.
Synergistic entinostat composition with an anti-CSF-1R antibody defined by heavy and light sequences
A method of treating cancer by administering to a patient a synergistic composition of entinostat and an anti-CSF-1R antibody or an antigen-binding fragment thereof, wherein the anti-CSF-1R antibody or the antigen-binding fragment thereof comprises a heavy chain comprising the sequence given in SEQ ID NO:23 with a variable domain comprising CDR-H1, CDR-H2, and CDR-H3 sequences given in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively, and a light chain comprising the sequence given in SEQ ID NO:15 with a variable domain comprising CDR-L1, CDR-L2, and CDR-L3 sequences given in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively.
Overall claim coverage is centered on treating cancer with entinostat in combination or as a synergistic composition with an anti-CSF-1R antibody/antigen-binding fragment defined by specific CDR sequences (independent claim 1) and by specified heavy and light chain sequences together with the same CDR sequences (independent claim 19). Additional claim refinements mentioned include antibody sequence embodiments, binding affinity constraints measured by surface plasmon resonance, specified administration relationships (simultaneous, concurrent, or sequential), and cancer-type scope limitations such as colorectal or pancreatic cancer.
Stated Advantages
Improved survival.
Tumor growth inhibition.
Increased CD8:Treg ratio.
Reduced intratumoral Tregs and TAMs.
Documented Applications
CT26 colon cancer example using entinostat together with Ab535, reporting improved survival and tumor growth inhibition along with immune profiling changes including increased CD8:Treg ratio and reduced intratumoral Tregs and TAMs.
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