Combination of a PD-1 antagonist and a RAF inhibitor for treating cancer
Inventors
Song, Jing • Wang, Lai • Li, Kang • Zhang, Tong • Luo, Lusong • Wei, Min • Tang, Zhiyu • Zhang, Guoliang • Zhou, Changyou
Assignees
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Publication Number
US-10864203-B2
Publication Date
2020-12-15
Expiration Date
Abstract
Disclosed herein is a pharmaceutical combination for use in the prevention, delay of progression or treatment of cancer, wherein the pharmaceutical combination exhibits a synergistic efficacy. The pharmaceutical combination comprises a humanized antagonist monoclonal antibody against PD- and a RAF inhibitor. Also disclosed herein is a combination for use in the prevention, delay of progression or treatment of cancer in a subject, comprising administering to the subject a therapeutically effective amount of a humanized antagonist monoclonal antibody against PD-1 and a therapeutically effective amount of a RAF inhibitor.
Core Innovation
The patent describes a cancer therapeutic pharmaceutical combination for treatment of lung cancer or colorectal cancer. The combination comprises a human PD-1-binding PD-1 antagonist and a RAF inhibitor administered as therapeutically effective amounts, linking the PD-1 pathway to tumor immune regulation and the RAF-MEK-ERK (MAPK) pathway to tumor signaling.
The PD-1 antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to human PD-1. The patent specifies the antagonist by heavy chain variable region and light chain variable region complementarity determining regions, including defined antibody variants and formats with optional antibody constant/effector domains, including IgG4 heavy chain effector/constant domains.
The RAF inhibitor is defined by chemical formulae, including compounds of Formula (II), Formula (H), and additional formula embodiments referenced in the claims, or pharmaceutically acceptable salts thereof. The combination is directed to administration that can be simultaneous, sequential, or separate.
The patent describes observed enhancement of IFN-γ production and inhibition of tumor growth with an anti-PD-1 antibody combined with a selective B-Raf inhibitor compared with monotherapy, and includes preclinical combination context in vitro and in vivo.
Claims Coverage
The provided independent claims cover two combination-therapy inventions for lung cancer or colorectal cancer, each centered on a sequence-defined human PD-1-binding antagonist and a formula-defined RAF inhibitor. The inventive features are organized around the same PD-1 antagonist definition combined with Formula (II) or Formula (H).
Sequence-defined human PD-1 binding PD-1 antagonist for combination therapy
An antibody or an antigen-binding fragment that specifically binds to human PD-1 and comprises a heavy chain variable region and a light chain variable region, wherein the Vh comprises CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 31, 32, and 33, respectively; and the Vk comprises CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 34, 35, and 36, respectively.
RAF inhibitor as a compound of Formula (II)
A RAF inhibitor that is a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
Pharmaceutical combination for lung cancer or colorectal cancer including PD-1 antagonist and RAF inhibitor
A pharmaceutical combination for use in the treatment of lung cancer or colorectal cancer comprising a PD-1 antagonist and a RAF inhibitor.
RAF inhibitor as a compound of Formula (H)
The RAF inhibitor is a compound of Formula (H), or a pharmaceutically acceptable salt thereof.
The claim set centers on a human PD-1-binding antibody defined by specific Vh/Vk CDR sequence identifiers combined with a RAF inhibitor defined by specific chemical formulae. The therapeutic framing is directed to lung cancer and colorectal cancer via administration or formulation of the PD-1 antagonist and RAF inhibitor as a combination.
Stated Advantages
Synergistic efficacy with enhanced IFN-γ production.
Inhibition of tumor growth with the combination versus monotherapy.
Documented Applications
Treatment of lung cancer.
Treatment of colorectal cancer.
In vitro PBMC/T cell spheroid results measuring IFN-γ in combination context.
In vivo synergy in K-Ras lung and B-Raf colon models using Compound 1 together with Mab 1.
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