Anti-MUC16 antibodies and uses thereof
Inventors
Spriggs, David • FERNANDEZ-TEJADA, Alberto • Thapi, Dharmarao
Assignees
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Publication Number
US-12466894-B2
Publication Date
2025-11-11
Expiration Date
Abstract
Provided herein are compositions, methods, and uses involving antibodies that immunospecifically bind glycosylated forms of MUC16, a tethered mucin protein. Also provided herein are uses and methods for managing, treating, or preventing disorders, such as cancer.
Core Innovation
The disclosure describes anti-MUC16 glycosylation-specific antibodies and antigen-binding fragments that recognize glycosylated extracellular epitopes of MUC16 and do not bind unglycosylated forms of MUC16. Binding is characterized in relation to glycosylated MUC16 forms, chitobiose-linked MUC16 glycopeptide epitopes, and N-glycosylated residues in C-terminal MUC16 fragments, including MUC16c114 and glycosylation-site mutants such as MUC16c114-N3, MUC16c114-N2, and MUC16c114-N23, with residues identified including Asn1806 and optionally Asn1800.
The antibodies are further defined by VH and VL CDR sequence patterns, including multiple lead antibodies and additional sequence-defined variants. The disclosure includes antibody formats including scFv, chimeric antigen receptor (CAR), bispecific antibody formats, including a bispecific antibody with CD3, and antibody conjugates where an anti-MUC16 antibody or antigen-binding fragment is conjugated to a payload.
The payload formats include imaging agent payloads with selectable detectable labels, cytotoxic agent payloads, and isotope label payloads. The antibodies and conjugates are associated with pharmaceutical, diagnostic, and therapeutic use, including cancer treatment and combination therapy using different glycosylation-epitope antibodies.
Claims Coverage
The independent claims center on anti-MUC16 antibody conjugates defined by specific VH and VL CDR amino-acid sequence patterns and a conjugated payload. Across the inventive features, the coverage includes CDR-defined antibody specificity, payload conjugation, imaging-agent and cytotoxic-agent payload options, isotope label payloads, and covalent or non-covalent conjugation.
Anti-MUC16 antibody conjugate with specified VH and VL CDR patterns
An anti-MUC16 antibody or antigen binding fragment is conjugated to a payload, wherein the antibody or fragment comprises defined VH CDR1, VH CDR2, VH CDR3, and VL CDR1, VL CDR2, VL CDR3 amino-acid sequence patterns, including explicit CDR sequences with variable-position constraints and alternative SEQ ID NO-referenced embodiments.
Payload conjugation to the antibody or antigen-binding fragment
The payload is conjugated to the anti-MUC16 antibody or antigen binding fragment, including covalent or non-covalent conjugation.
Imaging agent payload
The payload comprises an imaging agent, with detectable labels selected from chromogenic, enzymatic, radioisotopic, isotopic, fluorescent, chemiluminescent, or nuclear magnetic resonance contrast agent labels.
Cytotoxic agent payload
The payload comprises a cytotoxic agent.
Treatment of a MUC16-positive cancer by administering the pharmaceutical composition
A method of treating a MUC16-positive cancer in a patient in need thereof by administering an effective amount of a pharmaceutical composition.
The claim coverage centers on anti-MUC16 antibody or antigen-binding fragment conjugates defined by specific VH and VL CDR sequence patterns and attached to a payload. The coverage further distinguishes imaging-agent, cytotoxic-agent, and isotope-label payloads, specifies detectable label classes, includes covalent or non-covalent conjugation, and recites treatment of MUC16-positive cancer by administering the pharmaceutical composition.
Stated Advantages
Symptom improvement.
Survival benefits.
Inhibition of matrigel invasion in vitro of MUC16-glycosylated tumor cells.
Preferential binding to glycosylated MUC16-expressing cancer cells compared to unglycosylated forms.
Reduction of EGFR stabilization caused by induced MUC16 expression.
Tumor growth/metastasis effects including tumor regression.
Survival increase in mouse xenograft models.
Antibody internalization.
Binding to ovarian cancer tissue microarrays.
Documented Applications
Therapeutic treatment of MUC16-positive cancers, including ovarian cancer and other tissue-expressing cancers.
Diagnostic assays using labeled MUC16 glycosylation antibodies and imaging modalities including immunohistochemistry, ELISA, RIA, CT, PET, MRI, and sonography.
Cancer treatment using the disclosed anti-MUC16 antibody conjugates and pharmaceutical compositions.
Combination therapy using different glycosylation-epitope antibodies for cancer treatment.
Imaging and detection applications using an anti-MUC16 antibody conjugate with an imaging agent payload and selectable detectable labels.
Cell-based binding and characterization of anti-MUC16 glycosylation-directed monoclonal antibodies recognizing chitobiose-linked MUC16 glycopeptide epitopes at N24/N30.
Matrigel invasion assays showing inhibition of invasion of MUC16c114 and full-length MUC16+ ovarian cancer cells.
Assessment of EGFR stabilization effects caused by induced MUC16 expression.
Binding to ovarian cancer tissue microarrays.
Mouse flank xenograft studies showing decreased tumor growth or invasion and survival benefit in mouse xenograft models.
Imaging and detection using imaging agent payloads and isotope label payloads, including an 89Zr-labeled antibody.
In vitro inhibition of matrigel invasion of MUC16-glycosylated tumor cells.
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