Anti-integrin β1 antibody compositions and methods of use thereof
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Publication Number
US-11142576-B2
Publication Date
2021-10-12
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 describes a humanized antibody that specifically binds integrin β1. The antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, with the VH region having about 90–96% identity to a VH region having an amino acid sequence set forth in SEQ ID NO:2 and the VL region having about 84–92% identity to a VL region having an amino acid sequence set forth in SEQ ID NO:4. The CDR regions comprise SEQ ID NO:23–28.
The invention further provides composite human antibody designs based on a donor antibody OS2966 (murine), including anti-integrin β1 humanized antibody framework regions. The description includes competition binding assays versus integrin β1 and generation of scFv/Fab formats, and addresses deimmunisation by immunogenicity testing using EpiScreen™ with CD4+ T cell proliferation, including reduced immunogenicity for a composite variant H3 across HLA-DR allotypes.
Functionality and in vivo anti-tumor effects are documented across multiple models, including ECM adhesion/migration effects, in vitro angiogenesis, an orthotopic TNBC metastasis model using MDA-MB-231, a gemcitabine-resistant pancreatic cancer model using PANC1-GEMR, and a glioblastoma model using U87MG. Pharmacodynamic signaling pathway reductions are documented, including reduced pERK, pFAK, and pAKT signaling.
Claims Coverage
The claim coverage centers on one independent claim directed to a humanized antibody that specifically binds integrin β1, with identity ranges and CDR definition based on SEQ ID references. Dependent claims narrow performance and sequence details and extend the scope to immunoconjugates and use in treating integrin β1-expressing cancer.
Humanized antibody binding integrin β1 via defined VH/VL identity and CDRs
A humanized antibody specifically binds integrin β1 and comprises a VH region with about 90–96% identity to the VH sequence of SEQ ID NO:2 and a VL region with about 84–92% identity to the VL sequence of SEQ ID NO:4; the CDR regions comprise SEQ ID NO:23–28.
Binding affinity threshold against integrin β1
An antibody binds integrin β1 with an equilibrium dissociation constant (Kd) at least equal to one of the listed values.
Low CD4+ T cell response under human HLA-DR allotype distribution
A specified antibody is tested in vitro on blood samples containing a distribution of human HLA-DR allotypes and produces less than 10% of CD4+ helper T cell responses.
Specified VH and VL CDR sequences
An antibody is defined by VH-region CDRs comprising amino acid sequences specified as SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25, and VL-region CDRs comprising amino acid sequences specified as SEQ ID NO:26, SEQ ID NO:27, and SEQ ID NO:28.
Immunoconjugate with detectable or therapeutic moiety
An immunoconjugate is formed by linking the antibody of claim 1 to a moiety that is detectable or therapeutic.
Treatment of integrin β1-expressing cancer by administering the antibody
A method for treating integrin β1-expressing cancer in a subject by administering the antibody described in claim 1.
The core coverage is a humanized anti-integrin β1 antibody defined by VH/VL identity ranges to SEQ ID NO:2 and SEQ ID NO:4 and CDRs comprising SEQ ID NO:23–28, with dependent claim refinements including binding affinity, in vitro CD4+ helper T cell response thresholds, further CDR specification, immunoconjugates, and treatment of integrin β1-expressing cancer by administering the antibody.
Stated Advantages
Reduced immunogenicity as shown by in vitro CD4+ T cell proliferation results for a composite variant H3.
Anti-tumor effects documented across multiple in vitro and in vivo models.
Reduced pharmacodynamic signaling pathway activity including pERK, pFAK, and pAKT.
Documented Applications
Use in assays involving competition binding versus integrin β1.
Use of antibody formats including scFv and Fab.
Immunogenicity testing using EpiScreen™ with CD4+ T cell proliferation across HLA-DR allotypes.
Functional effects including ECM adhesion/migration and in vitro angiogenesis.
In vivo anti-tumor testing in an orthotopic TNBC metastasis model using MDA-MB-231.
In vivo anti-tumor testing in a gemcitabine-resistant pancreatic cancer model using PANC1-GEMR.
In vivo anti-tumor testing in a glioblastoma model using U87MG.
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