Filamin A binding proteins and uses thereof
Inventors
Wu, Wenfang Sybil • Ravipaty, Shobha • Friss, Tracey • Akmaev, Viatcheslav R. • Tanna, Nikunj Narendra
Assignees
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Publication Number
US-10759850-B2
Publication Date
2020-09-01
Expiration Date
Abstract
The present invention encompasses filamin A (FLNA) binding proteins. Specifically, the invention relates to antibodies to FLNA. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. Methods of making and methods of using the antibodies of the invention in methods of diagnosis, monitoring and prognosis of prostate cancer are also provided.
Core Innovation
The invention relates to FLNA-binding proteins, in particular anti-FLNA antibodies and antigen-binding fragments, including antibody constructs with defined heavy- and light-chain variable-region CDR domains. The binding specificity is defined by CDR1, CDR2, and CDR3 amino-acid sequences set forth in SEQ ID NOs, including SEQ ID NO: 7, 8, 9, 10, 11, and 12, and alternative CDR set identifiers.
The invention addresses diagnosing, monitoring, prognosing, risk assessment, and therapy-selection of abnormal prostate states, particularly prostate cancer and benign prostatic hyperplasia (BPH), based on detecting and comparing filamin A (FLNA) levels across sequential patient samples. It provides antibody compositions and reagents intended for detecting and measuring FLNA levels, and for using FLNA-related biomarker panels that include FLNA/FLNB and FLNA/KRT19 together with age and PSA.
The document further describes antibody construct components and related frameworks, including antibody constructs that contain linker polypeptides or immunoglobulin constant domains. It also describes nucleic acid/vector/host-cell production frameworks for expressing the antibodies or antigen-binding fragments, and diagnostic workflows using immunoassays, antibody-labeled fluorescence imaging, and mass-spectrometry approaches using FLNA surrogate peptides P2 and P4, including kit components and kit instructions for clinical use.
Claims Coverage
The provided independent claims define three core aspects: specific FLNA-binding antibody or antigen-binding fragment CDR sequence sets, optional antibody constructs and formulation/production context, and prostate-cancer diagnostic or prognostic kits based on detecting FLNA levels. Across the independent claims, the inventive features center on heavy-chain and light-chain CDR1/2/3 amino-acid sequences defined by SEQ ID NOs, with dependent refinements introducing binding-kinetics/affinity constraints and kit use for diagnosis, monitoring, or characterization of prostate cancer.
Specified FLNA-binding CDR sequence sets in antibody heavy and light variable regions
An antibody, or antigen-binding fragment thereof, capable of binding filamin A (FLNA), comprising a heavy chain variable region with CDR3 set forth in SEQ ID NO: 9, CDR2 set forth in SEQ ID NO: 8, and CDR1 set forth in SEQ ID NO: 7, and comprising a light chain variable region with CDR3 set forth in SEQ ID NO: 12, CDR2 set forth in SEQ ID NO: 11, and CDR1 set forth in SEQ ID NO: 10.
Specified FLNA-binding CDR sequence sets in antibody heavy and light variable regions
An antibody, or antigen-binding fragment thereof, capable of binding filamin A (FLNA), comprising a heavy chain variable region with CDR3 set forth in SEQ ID NO: 15, CDR2 set forth in SEQ ID NO: 14, and CDR1 set forth in SEQ ID NO: 13, and comprising a light chain variable region with CDR3 set forth in SEQ ID NO: 18, CDR2 set forth in SEQ ID NO: 17, and CDR1 set forth in SEQ ID NO: 16.
Specified FLNA-binding CDR sequence sets in antibody heavy and light variable regions
An antibody, or antigen-binding fragment thereof, capable of binding filamin A (FLNA), comprising a heavy chain variable region with CDR3 set forth in SEQ ID NO: 21, CDR2 set forth in SEQ ID NO: 20, and CDR1 set forth in SEQ ID NO: 19, and comprising a light chain variable region with CDR3 set forth in SEQ ID NO: 24, CDR2 set forth in SEQ ID NO: 23, and CDR1 set forth in SEQ ID NO: 22.
The claim set coverage is directed to FLNA-binding antibodies or antigen-binding fragments defined by specific heavy- and light-chain variable-region CDR1/2/3 amino-acid sequences using SEQ ID NOs. The dependent material further covers quantitative binding-kinetics and affinity constraints, antibody constructs with linker polypeptides or immunoglobulin constant domains, and diagnostic or prognostic kit use based on detecting FLNA levels for prostate cancer diagnosis, monitoring, or characterization.
Stated Advantages
Improved discrimination between prostate cancer and BPH compared with PSA alone, as supported by ROC analyses.
Predictive performance is improved by combining FLNA with PSA and/or keratin 19 and/or filamin B.
An increased FLNA level with no change is stated to indicate lack of efficacy or selection against active treatment.
Decreases in FLNA are stated to correlate with efficacious therapy.
Documented Applications
Diagnosing prostate cancer by detecting a level of FLNA using an antibody or antigen-binding fragment reagent in a diagnostic kit.
Monitoring prostate cancer using FLNA levels detected with an antibody or antigen-binding fragment reagent in a kit with instructions for clinical use.
Characterizing prostate cancer using FLNA levels detected with an antibody or antigen-binding fragment reagent in a diagnostic or prognostic kit.
Prostate abnormal state evaluation including prostate cancer and benign prostatic hyperplasia (BPH) using FLNA-related biomarker panels.
Immunoassay-based workflows using ELISA, RIA, immunohistochemistry, and antibody-labeled fluorescence imaging for detecting FLNA.
Mass-spectrometry-based workflows using FLNA surrogate peptides P2 and P4, including IPMRM/MRM approaches for FLNA detection.
Risk assessment, diagnosis, and monitoring of prostate cancer using FLNA levels detected in patient samples.
Prognostic and predictive medicine based on FLNA levels and their changes across sequential samples.
Clinical trial monitoring using FLNA-based detection.
Diagnostic/prognostic kit use for prostate cancer based on detecting a measured level of FLNA.
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