Antibodies against Frizzled receptor
Inventors
Sidhu, Sachdev • Gakhal, Amandeep • Pan, Guohua • Moffat, Jason • Robitaille, Melanie • Angers, Stephane
Assignees
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Publication Number
US-10689442-B2
Publication Date
2020-06-23
Expiration Date
Abstract
This invention provides monoclonal antibodies that recognize one or more Frizzled receptors. The invention further provides methods of using such monoclonal antibodies as a therapeutic, diagnostic, and prophylactic.
Core Innovation
The invention relates to an isolated antibody or antigen-binding fragment thereof that binds to one or more Frizzled receptors and prevents the one or more Frizzled receptors from binding to a Wnt protein ligand. The antibodies are defined by specific variable light chain and variable heavy chain complementarity determining regions, including a variable light chain CDRL1 comprising SEQ ID NO: 392 and a variable light chain CDRL2 comprising SEQ ID NO: 393, together with specified CDRL3, CDRH1, CDRH2, and CDRH3 sequences. These binding and prevention functions are directed to Frizzled receptor–Wnt ligand interaction blockade.
The described antibodies and antigen-binding fragments bind Frizzled receptors, including FZD7 and also referenced Frizzled receptors such as FZD1–FZD6 and FZD8–FZD10. The binding blocks Wnt ligand binding and inhibits Wnt signaling, including inhibition of Wnt5a binding and inhibition of Wnt3a-induced transcriptional activity using a transcription reporter assay. The inhibition of Wnt signaling supports use in contexts where Wnt signaling is dysregulated.
The patent content additionally describes anti-Frizzled receptor monoclonal antibodies and antigen-binding fragments with therapeutic, diagnostic, and prophylactic utility. The applications discussed include cancers and other dysregulated disorders, including bone diseases such as osteoporosis, osteoarthritis, and rheumatoid arthritis, where aberrant Frizzled receptor expression or activity is implicated. The document also includes characterization of binding and function and reports anti-tumor efficacy in pancreatic cancer cell lines and mouse xenograft models, consistent with preventing Frizzled receptors from binding Wnt protein ligands and inhibiting Wnt signaling.
Claims Coverage
The partial content provides one independent claim (clm-00001). The dependent claims refine the antibody format and extend to pharmaceutical compositions and therapeutic administration, including selected cancer types.
Antibody with specified Frizzled-blocking CDR sequences
An isolated antibody or antigen-binding fragment that binds one or more Frizzled receptors and prevents the one or more Frizzled receptors from binding to a Wnt protein ligand, where the antibody comprises CDRL1 SEQ ID NO: 392, CDRL2 SEQ ID NO: 393, CDRL3 SEQ ID NO: 132, CDRH1 SEQ ID NO: 133, CDRH2 SEQ ID NO: 134, and CDRH3 SEQ ID NO: 135.
Across the provided claim set, coverage centers on an isolated antibody or antigen-binding fragment defined by specific CDR sequences that block Frizzled receptor binding to Wnt protein ligands, thereby preventing the Frizzled receptor–Wnt ligand interaction central to Wnt signaling inhibition. Dependent claims further specify IgG/IgG1 formats, add pharmaceutical composition with a carrier, and cover administering the antibody to alleviate symptom(s) of diseases or disorders linked to aberrant Frizzled receptor expression or activity, including administration for selected cancer types.
Stated Advantages
Blocks one or more Frizzled receptors from binding to Wnt protein ligand.
Inhibits Wnt signaling, including inhibition of Wnt ligand binding and inhibition of Wnt3a-induced transcriptional activity.
Alleviates symptoms of diseases or disorders associated with aberrant Frizzled receptor expression or activity.
Documented Applications
Therapeutic use for cancers, including pancreatic cancer and other cancers selected from a defined list.
Therapeutic or prophylactic utility for bone diseases, including osteoporosis, osteoarthritis, and rheumatoid arthritis.
Diagnostic use is described as a utility of the antibodies or antigen-binding fragments.
Pharmaceutical composition use is described in the presence of a carrier.
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