Anti-integrin β1 antibody compositions and methods of use thereof
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Publication Number
US-10023638-B2
Publication Date
2018-07-17
Expiration Date
Abstract
The current invention provides human variable chain framework regions and humanized antibodies comprising the framework regions, the antibodies being specific for integrin β1. The invention also provides methods for utilizing the antibodies, for example to treat diseases such as cancer.
Core Innovation
The invention is directed to anti-integrin α11 humanized antibodies that specifically bind integrin α11. The antibodies comprise a heavy chain variable (VH) region and a light chain variable (VL) region, with VH and VL amino acid sequences set forth in SEQ ID NO combinations. Humanization uses human VH/VL framework regions with CDRs grafted from OS2966, including embodiments with specified sequence-identity combinations.
The described antibodies and related compositions include nucleic acid molecules, vectors, and isolated host cells for expressing the humanized antibodies, as well as pharmaceutical compositions and immunoconjugates. Immunoconjugates link the antibody to detectable or therapeutic moieties, and antibody formats include chimeric protein formats and Fc-region-containing proteins, including immunoglobulin subclasses.
The disclosure states that composite human antibody variants show functional inhibition of ECM adhesion, migration, and angiogenesis in vitro, and reduce tumor growth and metastasis in orthotopic xenograft models. The disclosure further describes deimmunization using T-cell epitope filtering, including EpiScreen, intended to reduce immunogenicity, with reported reduced CD4+ T-cell responses compared to a chimeric control.
Claims Coverage
The claim coverage centers on one independent claim for a humanized anti-integrin α11 antibody defined by specified VH and VL amino acid sequence combinations, with additional claim features refining binding affinity, immunogenicity, immunoconjugate format, multi-specific inclusion, and Fc-region subclass options.
Humanized antibody binding integrin α11 with specified VH and VL sequences
A humanized antibody which specifically binds integrin α11 comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH and the VL regions have amino acid sequences as set forth in SEQ ID NO combinations.
Defined binding affinity (Kd threshold range)
The antibody has an equilibrium dissociation constant (Kd) of at least one of the specified values spanning 10^-2 M through 10^-10 M.
Reduced CD4+ T-cell response across HLA-DR allotypes
The antibody, when tested in vitro, induces CD4+ helper T cell responses in blood samples spanning human HLA-DR allotypes at a level of less than 10% of T cell responses.
Immunoconjugate linking the antibody to a detectable or therapeutic moiety
An immunoconjugate made by linking the antibody of the humanized integrin α11 binding claim to a detectable moiety or a therapeutic moiety.
Multi-specific antibody including the defined humanized antibody
A multi-specific antibody that includes the antibody described in the integrin α11 humanized antibody claim.
Fc region IgG subclass restriction
An antibody wherein the Fc region is of the IgG1, IgG2, IgG3, or IgG4 subclass.
The claims are directed to a humanized antibody that specifically binds integrin α11 via specified VH/VL SEQ ID NO combinations, further limited by binding-affinity thresholds, reduced CD4+ T-cell responses, immunoconjugate and multi-specific formats, and Fc-region IgG subclass restrictions.
Stated Advantages
Inhibits ECM adhesion, migration, and angiogenesis in vitro.
Reduces tumor growth and metastasis in orthotopic xenograft models.
Exhibits reduced immunogenicity, including reduced CD4+ T-cell responses compared to a chimeric control.
Documented Applications
Treatment of cancer by targeting integrin α11, including triple-negative breast cancer, gemcitabine-resistant pancreatic cancer, and glioblastoma.
Detection of integrin α11 in samples using labeled antibodies.
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