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-11534431-B2
Publication Date
2022-12-27
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 invention relates to a synergistic pharmaceutical combination for the delay of progression or treatment of cancer. It combines a PD-1 antagonist with a RAF inhibitor, where the cancer is associated with a B-Raf mutation or a K-Ras mutation, and the cancer is identified as lung cancer or colon cancer.
The PD-1 antagonist is described as an antibody or an antigen binding fragment thereof that specifically binds to human PD-1. The antibody is humanized and comprises a heavy chain variable region (Vh) and a light chain variable region (Vk) with complementarity determining regions CDR1, CDR2, and CDR3.
The RAF inhibitor is described as a selective RAF inhibitor, including compounds of Formula (I) and related formula sets such as Formula (II) maleate, Formula (III), and Formula (IIIa). The combination is stated to yield synergistic effects including enhanced IFN-γ and improved tumor growth inhibition compared with monotherapy.
Claims Coverage
The document contains two independent claims directed to methods that delay cancer progression or treat cancer by administering a therapeutically effective amount of a PD-1 antagonist in combination with a therapeutically effective amount of a RAF inhibitor. Across the two independent claims, the inventive features are organized around the combination therapy, the mutation- and cancer-type limitations, and specific structural definitions and compound/formula limitations for the PD-1 antagonist and RAF inhibitor.
Combination therapy for delaying progression or treating cancer
A method for the delay of progression or treatment of cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a PD-1 antagonist in combination with a therapeutically effective amount of a RAF inhibitor.
Mutation- and cancer-type limitation
Wherein the cancer is associated with a B-Raf mutation or a K-Ras mutation, wherein the cancer is a lung cancer or a colon cancer.
Human PD-1-binding antibody definition with specified CDR SEQ ID Nos
Wherein the PD-1 antagonist is an antibody or an antigen binding fragment thereof, which specifically binds to human PD-1 and which comprises a heavy chain variable region (Vh) and a light chain variable region (Vk), wherein the Vh comprises CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 31, 32, and 33, respectively; and the Vk comprises CDR1, CDR2, CDR3 comprising SEQ ID NOs: 34, 35, and 36, respectively.
RAF inhibitor as a compound of Formula (I)
Wherein the RAF inhibitor is a compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
IgG4 PD-1 antagonist with defined effector or constant domain and variable regions
Wherein the PD-1 antagonist is an antibody which comprises a heavy chain variable region (Vh), a light chain variable region (Vk), and an IgG4 heavy chain effector or constant domain comprising SEQ ID NO: 88, wherein the heavy chain variable region (Vh) and the light chain variable region (Vk) comprise SEQ ID NO: 24 and SEQ ID NO: 26, respectively.
RAF inhibitor as compound of Formula (IIIa)
Wherein the RAF inhibitor is the compound of Formula (IIIa).
Across the independent claims, the core claimed inventive concept is a synergistic combination method administering a therapeutically effective amount of a PD-1 antagonist with a therapeutically effective amount of a RAF inhibitor to delay progression or treat lung or colon cancer associated with B-Raf or K-Ras mutations. The PD-1 antagonist is structurally limited to human PD-1-binding antibodies with specified Vh/Vk CDR SEQ ID-defined regions in one independent claim, and to an IgG4 format with defined effector or constant domain and defined variable regions in the other. The RAF inhibitor is limited to specific compound definitions, including Formula (I) or Formula (IIIa).
Stated Advantages
Synergistic effects when combining the anti-PD-1 antibody with the selective RAF inhibitor.
Enhanced IFN-γ.
Improved tumor growth inhibition compared with monotherapy.
Documented Applications
Prevention or delay of cancer progression or treatment of cancer in a subject, where the cancer is lung cancer or colon cancer associated with B-Raf or K-Ras mutation.
The combination is presented with particular emphasis for K-Ras-mutation-associated cancers.
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