DLL3-targeting antibodies and uses thereof
Inventors
POIRIER, John T. • RUDIN, Charles • Lewis, Jason • Khan, Abdul • Andrew, David • Chen, Xinlei • Lorenz, Ivo
Assignees
Memorial Sloan Kettering Cancer Center • Tri Institutional Therapeutics Discovery Institute Inc
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Publication Number
US-12441789-B2
Publication Date
2025-10-14
Expiration Date
Abstract
The present disclosure relates generally to immunoglobulin-related compositions (e.g., antibodies or antigen binding fragments thereof) that can bind to delta-like protein 3 (DLL3). The antibodies of the present technology are useful in methods for detecting and treating a DLL3-associated cancer in a subject in need thereof.
Core Innovation
The patent describes an antibody or antigen binding fragment comprising a heavy chain immunoglobulin variable domain and a light chain immunoglobulin variable domain. The V_H comprises V_H-CDR1, V_H-CDR2, and V_H-CDR3 sequences selected from specific sets of SEQ ID NOs, and the V_L comprises V_L-CDR1, V_L-CDR2, and V_L-CDR3 sequences selected from specific sets of SEQ ID NOs. The antibody or antigen binding fragment can include Fc domain formats and isotypes, and sequence identity constrained variants are also described.
The disclosed antibodies bind to an epitope present in a mammalian DLL3 polypeptide and are used in DLL3 binding assays and for detecting DLL3 protein levels. The document also describes DLL3 internalization for payload delivery and references binding characterization, including binding curves and KD calculations. Assay concepts include comparing binding under control conditions and quantifying binding improvement using a usefulness threshold of at least 1% binding improvement.
The patent connects these DLL3-binding antibodies and fragments to diagnostic and therapeutic use cases. Diagnostic concepts include detecting DLL3 protein levels in biological samples using detectable labels including radioactive, fluorescent, and chromogenic labels, along with kit embodiments and labeled immunoassay formats. Therapeutic use is described for DLL3-associated cancers, including small cell lung carcinoma, large cell neuroendocrine carcinoma, extrapulmonary neuroendocrine cancers, and melanoma.
Claims Coverage
The independent claim coverage centers on a DLL3-binding antibody or antigen binding fragment defined by specific VH-CDR1/2/3 and VL-CDR1/2/3 sequence selections from enumerated SEQ ID NO groups. Across the items, the inventive features also include sequence-identity variants, Fc isotype scope, DLL3 epitope binding, detectable-label kit embodiments, and detecting DLL3 protein levels in biological samples.
Cdr-defined VH and VL variable domains
An antibody or antigen binding fragment comprising a heavy chain immunoglobulin variable domain and a light chain immunoglobulin variable domain, wherein the V_H comprises V_H-CDR1, V_H-CDR2, and V_H-CDR3 sequences selected from enumerated groups of SEQ ID NOs, and the V_L comprises V_L-CDR1, V_L-CDR2, and V_L-CDR3 sequences selected from enumerated groups of SEQ ID NOs.
Sequence identity constrained variants
A light chain immunoglobulin variable domain sequence at least 95% identical to one of specified SEQ ID NOs and a heavy chain immunoglobulin variable domain sequence at least 95% identical to one of specified SEQ ID NOs.
Fc domain isotype options
The antibody or antigen binding fragment includes an Fc domain with an isotype selected from IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgD, or IgE.
Dll3 epitope binding
The antibody or antigen binding fragment binds to an epitope present in a mammalian DLL3 polypeptide.
Detectable-label kit embodiment
A kit in which the antibody or antigen binding fragment is coupled to at least one detectable label chosen from radioactive, fluorescent, or chromogenic labels.
Detecting DLL3 protein levels
A method of detecting DLL3 protein levels in a biological sample by contacting the sample with an antibody or antigen binding fragment conjugated to a detectable label and detecting the signal from the label.
Overall, the claim coverage is directed to antibodies defined by specific V_H and V_L CDR sequence selections, with further narrowing to DLL3 epitope binding and optional refinements including sequence-identity variants, Fc isotype scope, detectable-label kit embodiments, and detecting DLL3 protein levels in biological samples.
Stated Advantages
Provides measurable binding improvement using a usefulness threshold of at least 1% binding improvement.
Enables DLL3 protein detection in biological samples using detectable-label signal detection.
Supports diagnostic use through multiple labeled immunoassay formats, including radioimaging-related approaches.
Documented Applications
DLL3 binding assays using an anti-DLL3 antibody with DLL3 protein and control conditions, quantified across multiple assay modalities including ELISA, radioimmunoassay, scintillation proximity assay, fluorescence, FRET, SPR, BIAcore, BLI, and 2D-NMR.
DLL3 localization and quantitation using anti-DLL3 antibody-based approaches.
Purification of DLL3-related components using affinity and immunoprecipitation approaches.
Detecting DLL3 protein levels in a biological sample using labeled antibody conjugates and signal detection.
Diagnostic applications for DLL3-associated cancers, including imaging-related use with radioisotope-labeled antibodies.
Therapeutic administration for DLL3-associated cancers, including small cell lung carcinoma, large cell neuroendocrine carcinoma, extrapulmonary neuroendocrine cancers, and melanoma.
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