Method of treating an interleukin-11-associated or -mediated fibrotic disease or condition by administering an anti-interleukin-11 receptor subunit alpha (IL-11RA) antibody
Inventors
Horlick, Robert A. • Jun, Helen Toni • King, David J.
Assignees
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Publication Number
US-12365738-B2
Publication Date
2025-07-22
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 disclosure describes a method of treating an IL-11-associated or IL-11-mediated fibrotic disease or condition in a subject by administering an antibody or an antigen binding fragment thereof that binds interleukin-11 receptor subunit alpha (IL-11Ralpha). The antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL) having defined complementary determining region (CDR) sequences, with multiple specified SEQ ID NO sets.
The antibodies or antigen-binding fragments bind human IL-11Ralpha, including membrane-bound IL-11Ralpha, and the binding can be directed to a fibronectin type-III domain approximately residues 112-219 of SEQ ID NO: 257. In functional terms described in the provided content, the IL-11Ralpha-binding antibodies exhibit IL-11Ralpha antagonism and inhibit STAT3 and ERK signaling.
The disclosure also provides pharmaceutical compositions and describes formulation-related attributes such as sterility, injectable presentation, and reduced glycoheterogeneity. It further describes optional Fc domain classes and effector function considerations, including IgG1/IgG4 and low-effector IgG options, together with engineered Fc modifications that affect effector function and/or half-life.
Claims Coverage
The independent claim coverage centers on administering an IL-11Ralpha-binding antibody or antigen-binding fragment for treating an IL-11-associated or IL-11-mediated fibrotic disease or condition, with six inventive features recited across the inputs.
IL-11Ralpha-binding antibody or antigen-binding fragment for treating IL-11-associated fibrotic disease
A method of treating an IL-11-associated or IL-11-mediated fibrotic disease or condition in a subject by administering an antibody, or antigen binding fragment thereof, that binds IL-11Ralpha, wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL).
VH and VL CDR sequence sets defined by multiple SEQ ID NOs
The VH and VL CDR sequences are defined by multiple specified SEQ ID NO sets, with VH comprising CDR1, CDR2, and CDR3 sequences and VL comprising CDR1, CDR2, and CDR3 sequences.
Fibronectin domain III / defined IL-11Ralpha epitope
The antibody or antigen-binding fragment binds a fibronectin domain III of human IL-11Ralpha or approximately residues 112-219 of SEQ ID NO: 257.
Human IgG1 or IgG4 Fc domain specification
The antibody contains a human IgG1 or IgG4 Fc domain, including hybrid, variant, or modified Fc domains, optionally where the human IgG4 Fc domain comprises SEQ ID NO: 258 or 259.
Modified Fc domain with low effector function in humans
The antibody contains a modified Fc domain that shows low effector function in humans.
Modified Fc substitutions M252Y, S254T, and T256E
The modified Fc domain contains substitutions M252Y, S254T, and T256E, or residues corresponding to them, versus the wild-type Fc sequence (EU numbering).
Overall, the claims coverage centers on IL-11Ralpha-antagonizing antibodies and antigen-binding fragments defined by specified VH/VL CDR SEQ ID NO sets, with additional narrowing to a fibronectin domain III epitope and Fc class or Fc engineering features.
Stated Advantages
Very high affinity binding in the pM range to human IL-11Ralpha.
Improved potency relative to comparator antibodies TS7/8E2.
IL-11Ralpha antagonism and inhibition of STAT3 and ERK signaling.
Optional reduction in N-linked glycosylation in VL CDR3.
Reduced glycoheterogeneity in pharmaceutical compositions.
Engineered Fc modifications to affect effector function and/or half-life.
Optional low-effector function in humans for modified Fc embodiments.
Documented Applications
Treatment of IL-11-associated fibrotic disease or condition.
Treatment of IL-11-associated or IL-11-mediated fibrotic disease or condition in a subject in need thereof.
Treatment of inflammatory conditions.
Treatment of autoimmune diseases.
Treatment of cancer conditions.
Treatment of wasting disease.
Treatment of bone disease.
Treatment of fibrosis.
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