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Publication Number
US-12209134-B2
Publication Date
2025-01-28
Expiration Date
Abstract
Provided is an anti-human Fn14 antibody which binds to human Fn14 to inhibit an action via the human Fn14, thereby preventing or treating cancer cachexia.The inventors have conducted studies on an anti-human Fn14 antibody, and provided an anti-human Fn14 antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 2 and a light chain consisting of the amino acid sequence of SEQ ID NO: 4.
Core Innovation
The invention relates to an anti-human Fn14 antagonist antibody and antigen-binding fragments that bind Fn14 (TNFRSF12A/Tweak receptor, Tweak receptor). The antibody is defined by specific heavy-chain and light-chain CDR sequences taken from SEQ ID NO: 2 and SEQ ID NO: 4, respectively, including CDR1, CDR2, and CDR3 defined by specified amino-acid positions. The antibody further includes optional posttranslational modifications, including pyroglutamylation at the heavy-chain VH N-terminus and/or deletion of a C-terminal lysine.
The disclosed antibodies, including fully humanized (4-1h) and murinized (4-1m) forms, bind human and mouse Fn14. The antibodies inhibit Tweak-induced NFkB activation without agonist activity and suppress IL-8 production induced by Tweak. This profile is presented as antagonist activity directed to Fn14 signaling in the context of Tweak.
In C26 mouse cancer cachexia models, 4-1m suppresses weight loss, increases muscle mass, and increases grip strength while prolonging survival. The document further reports that combination treatment with gemcitabine increases median survival without affecting tumor volume. These outcomes are presented in the context of the colon cancer cachexia model and survival measurements.
Claims Coverage
The independent claim set in the provided material includes one independent claim (clm-00001), which defines an anti-human Fn14 antibody or antigen-binding fragment by specific heavy- and light-chain CDR amino-acid sequences. The dependent claim set mainly refines the antibody/fragment format and adds optional posttranslational modification and related biomedical use claims.
Anti-human Fn14 antibody defined by specific heavy- and light-chain CDR sequences
An anti-human Fn14 antibody or antigen-binding fragment comprising a heavy chain variable region with CDR1, CDR2, and CDR3 defined by amino-acid sequences taken from specified positions of SEQ ID NO: 2, and a light chain variable region with CDR1, CDR2, and CDR3 defined by amino-acid sequences taken from specified positions of SEQ ID NO: 4.
Across the provided independent claim, the core inventive aspect is the precise specification of Fn14-binding heavy- and light-chain variable CDR sequences using defined amino-acid ranges from SEQ ID NO: 2 and SEQ ID NO: 4. Additional refinements described in the provided claim family include optional posttranslational modifications and use extensions, with a specific indication reported for colon cancer cachexia.
Stated Advantages
Inhibits Tweak-induced NFkB activation without agonist activity.
Suppresses IL-8 production induced by Tweak.
In C26 mouse cancer cachexia models, suppresses weight loss.
Increases muscle mass and grip strength in C26 mouse cancer cachexia models.
Prolongs survival in C26 mouse cancer cachexia models.
Increases median survival when combined with gemcitabine without affecting tumor volume.
Documented Applications
Treatment of colon cancer cachexia by administering a therapeutically effective amount of an anti-human Fn14 antibody or antigen-binding fragment.
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