Anti-CD30L antibodies and uses thereof
Inventors
Fecteau, Jessie-Farah • Renshaw, Mark • Fransson, Johan • Laurent, Olivier • Barnett, Burton
Assignees
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Publication Number
US-11866505-B2
Publication Date
2024-01-09
Expiration Date
Abstract
Described herein are anti-CD30L antibodies and pharmaceutical compositions for the treatment of autoimmune diseases and disorders such inflammatory bowel disease (IBD), including Crohn's Disease (CD) and ulcerative colitis (UC).
Core Innovation
The invention relates to anti-CD30L antibodies and antigen-binding fragments thereof that bind CD30L (CD153/TNFSF8). The antibodies are defined by specific heavy chain and light chain complementarity determining regions, including CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences referenced by SEQ ID NOs, with multiple alternative CDR sets recited in the disclosure.
A central aspect is inhibiting CD30L-CD30 interaction, thereby inhibiting CD30 signaling and reducing immune activation. The inhibition is associated with decreased pro-inflammatory cytokine expression or secretion, including IL-6 and IL-8, and the antibodies are characterized by binding performance and affinity metrics such as KD, kon, and koff.
The disclosure further includes Fc and constant-region features intended to reduce immunogenicity and effector functions, including reduced ADCC and reduced CDC relative to human IgG1. The specification also addresses IgG constant region features, IgG subclasses, germline reversion, cysteine engineering, and epitope mapping of anti-CD30L antibodies by cross-linking and mass spectrometry.
Claims Coverage
The independent claim coverage is focused on a CD30L-binding antibody or antigen-binding fragment defined by specified CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 amino-acid sequences, with multiple alternative CDR sequence sets provided by SEQ ID NOs. Additional claim features in the provided coverage include VH/VL sequence identity, IgG constant-region sequence identity, reduced ADCC and/or reduced CDC relative to human IgG1, and selection among IgG1 through IgG4.
CD30L binding antibody with defined CDR-H and CDR-L sequence sets
An antibody or antigen-binding fragment that binds CD30L and comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, with alternative sequence sets defined by SEQ ID NOs.
Defined VH and VL sequence identity relative to specified SEQ IDs
An antibody or antigen-binding fragment wherein VH and VL amino acid sequences each share at least about 90% sequence identity with specified SEQ ID numbers.
IgG constant region defined by sequence identity to specified SEQ IDs
An IgG antibody or antigen-binding fragment having an IgG constant region with an amino acid sequence with 95% sequence identity to the amino acid sequence set forth by any one of SEQ ID NOs 500-512.
Reduced ADCC and/or reduced CDC relative to human IgG1
An antibody or antigen-binding fragment having an IgG constant region with reduced antibody-dependent cell-mediated cytotoxicity and/or reduced complement-dependent cytotoxicity relative to human IgG1.
Selected IgG subclass
An IgG antibody that is specifically IgG1, IgG2, IgG3, or IgG4.
The inventive coverage is centered on CD30L-binding antibodies or antigen-binding fragments defined by specified CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences, together with sequence-identity and constant-region constraints, reduced ADCC/CDC relative to human IgG1, and selected IgG subclasses.
Stated Advantages
Blocking of CD30–CD30L interaction.
Blocking of CD30L-mediated signaling.
Reduction of CD30L-mediated IL-8 release.
Decreased pro-inflammatory cytokine expression or secretion, including IL-6 and IL-8, associated with inhibition of CD30L-CD30 interaction.
Reduces ADCC activity compared to human IgG1.
Reduces CDC activity compared to human IgG1.
Provides quantitative reductions in immunologic effector activity, including cases with no detectable activity.
Reduced immunogenicity, as described via reduced or low effector functions through Fc variants and constant-region constraints.
Documented Applications
Use of CDC assays to evaluate complement-dependent cytotoxicity (CDC) as a mechanism relevant to the described antibodies.
Methods of inhibiting CD30L-CD30 binding and inhibiting CD30 signaling in an individual.
Use in reducing pro-inflammatory cytokine expression or secretion in an individual, including IL-6 and IL-8.
Treatment of autoimmune disease, particularly inflammatory bowel disease, including Crohn’s disease and ulcerative colitis.
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