Anti-interleukin-11 receptor subunit α (IL-11Rα) antibodies
Inventors
Horlick, Robert A. • Jun, Helen Toni • King, David J.
Assignees
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Publication Number
US-12129303-B2
Publication Date
2024-10-29
Expiration Date
Abstract
Provided are antibodies and antigen binding fragments thereof that bind to human interleukin-11 receptor subunit α (IL-11Rα) and related compositions, which may be used in any of a variety of therapeutic or diagnostic methods, including the treatment or diagnosis of cancers, inflammatory diseases, autoimmune diseases, and others.
Core Innovation
The invention relates to interleukin-11 receptor subunit (IL-11R)-binding isolated antibodies or antigen binding fragments. The antibodies are defined by heavy chain variable region (VH) and light chain variable region (VL) complementary determining region (CDR) sequences, including multiple alternative sets of VH CDR1, CDR2, and CDR3 sequences and VL CDR1, CDR2, and CDR3 sequences specified by SEQ ID NOs. The antibodies bind IL-11R and are described as IL-11R antagonists that block IL-11R/IL-11 binding and signaling.
The disclosed IL-11R antagonist activity is characterized by inhibiting STAT3 phosphorylation and IL-11R-gp130 dimerization or complex formation. Functional assessment is described using cell-based assays that include STAT3 reporter, Western blot, and FACS approaches. In IL-11R+gp130 cell models, the antibodies are described as reducing cell proliferation.
The document further describes anti-fibrotic application in precision-cut lung slices (PCLS), including effects on extracellular-matrix remodeling biomarkers such as PRO-C6 and type VI collagen. Fc region options are provided, including specified immunoglobulin classes and subclasses, with human IgG4 configurations discussed along with examples of Fc engineering, and therapeutic method and use coverage is provided for IL-11-associated diseases including cancer and fibrotic diseases.
Claims Coverage
The provided materials include one independent claim that defines an IL-11R-binding antibody or antigen binding fragment by binding and by multiple alternative VH/VL CDR sequence sets. Dependent claims add IL-11R domain specificity, humanization/Fc mutation, selected binder formats, and a pharmaceutical composition with a pharmaceutically acceptable carrier.
IL-11R-binding antibody defined by VH and VL CDR sequence sets
An isolated antibody, or an antigen binding fragment thereof, that binds interleukin-11 receptor subunit IL-11R, comprising VH and VL regions with VH CDR1, VH CDR2, VH CDR3 and VL CDR1, VL CDR2, VL CDR3 sequences defined by multiple alternative SEQ ID NO combinations.
Human IL-11R fibronectin domain III binding region specificity
The isolated antibody, or an antigen binding fragment thereof, binds to human IL-11R fibronectin domain III, or to approximately residues 112–219 of SEQ ID NO:257.
Humanized antibody with IgG4 Fc and S228P mutation
An isolated humanized antibody, or an antigen binding fragment, optionally as a humanized monoclonal antibody containing a human IgG4 Fc domain with an S228P mutation.
Selected antibody/binder formats
An isolated antibody, or an antigen binding fragment, selected from specified binder/antibody types including Fv and scFv and additional alternative binding protein formats.
Pharmaceutical composition including antibody or fragment and pharmaceutically acceptable carrier
A pharmaceutical composition including a pharmaceutically acceptable carrier and the isolated antibody, or an antigen binding fragment, as defined in claim 1.
Overall, the claims coverage centers on an IL-11R-binding isolated antibody or antigen binding fragment defined by specific VH/VL CDR sequence sets, with dependent embodiments narrowing IL-11R binding to the fibronectin domain III region, specifying a humanized IgG4 Fc with an S228P mutation, limiting allowed binder formats, and providing a pharmaceutical composition embodiment.
Stated Advantages
IL-11R antagonism, including blocking IL-11R–IL-11 binding and signaling such as STAT3 phosphorylation.
Reduced IL-11R dimerization or complex formation.
Improved developability, including reduced N-linked glycosylation heterogeneity in a VL CDR3 region.
Aggregate/endotoxin-free composition characteristics.
Reduces cell proliferation in IL-11R+gp130 cell models.
Shows anti-fibrotic activity in precision-cut lung slices, including decreased extracellular-matrix remodeling biomarkers such as PRO-C6/type VI collagen.
Documented Applications
Therapeutic indications for cancers.
Therapeutic indications for inflammatory diseases.
Therapeutic indications for autoimmune diseases.
Therapeutic indications for wasting/bone diseases.
Therapeutic indications for fibrotic conditions, including lung ILD/IPF subsets.
IL-11-associated diseases including cancer.
Fibrotic diseases, including use supported by anti-fibrotic activity in precision-cut lung slices with extracellular-matrix remodeling biomarker effects.
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