Human estrogen receptor specific immunoglobulin for use in treatment and prevention of cell proliferative disorders
Inventors
Schoeberl, Birgit • Nielsen, Ulrik • Feldhaus, Michael • Muruganandam, Arumugam • Buckler, David
Assignees
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Publication Number
US-7846440-B2
Publication Date
2010-12-07
Expiration Date
Abstract
The present invention provides a novel class of monoclonal antibodies which bind ErbB3 receptor and inhibits various ErbB3 functions. In a particular embodiment, the antibodies are capable of binding to ErbB3 and inhibiting ligand mediated phosphorylation of the receptor.
Core Innovation
The invention relates to an isolated full length IgG monoclonal antibody that binds to ErbB3 and inhibits ErbB3 signaling relevant to cancers. The antibody is defined to bind ErbB3 with a dissociation constant (K_D) of about 4 nM, as measured using a surface plasmon resonance assay or a cell binding assay using MALME-3M cells. The ErbB3-directed binding is linked to inhibition of EGF-like ligand-mediated ErbB3 phosphorylation and downstream pathway activity.
The disclosed antibodies comprise specified heavy chain variable region and light chain variable region sequences (SEQ ID NO:1 and SEQ ID NO:2) and can further be characterized by heavy and light chain CDR sequences (SEQ ID NO:7 to SEQ ID NO:12). The described inhibition includes effects on ErbB3 downregulation/internalization and suppression of signaling associated with heregulin and other EGF-like ligands. Downstream effects described include reduced ErbB3-related phosphorylation and reduced AKT phosphorylation in cell models.
The patent content further connects the ErbB3 signaling inhibition to functional outcomes including decreased VEGF secretion, reduced cell migration, and reduced spheroid growth, and it also reports inhibition of tumor growth in xenograft models. Specific example antibodies are described as producing reductions in relevant signaling readouts and tumor growth, with dose-dependent effects described in vivo.
Claims Coverage
The provided excerpt includes eight independent claims directed to isolated full length IgG monoclonal antibodies that bind ErbB3 and are further defined by sequence (variable-region and/or CDR) constraints and/or functional signaling readouts. Across the independent claims, the inventive features include ErbB3 binding with a specified K_D, ErbB3 downregulation on MALME-3M cell surfaces, inhibition/potency against betacellulin-mediated ErbB3 phosphorylation (IC50 range), and inhibition of heregulin-mediated AKT phosphorylation at a specified concentration, with some claims adding defined CDR composition.
ErbB3-binding IgG with specified heavy and light variable regions
An isolated full length IgG monoclonal antibody that binds to ErbB3 with a K_D of about 4 nM as measured using a surface plasmon resonance assay or a cell binding assay using MALME-3M cells, and comprises a heavy chain variable region sequence as set forth in SEQ ID NO:1 and a light chain variable region sequence as set forth in SEQ ID NO:2.
ErbB3-binding IgG with specified CDR sequences
An isolated full length IgG monoclonal antibody that binds to ErbB3 with a K_D of about 4 nM as measured using a surface plasmon resonance assay or a cell binding assay using MALME-3M cells, and comprises a heavy chain variable region CDR1 comprising SEQ ID NO:7; a heavy chain variable region CDR2 comprising SEQ ID NO:8; a heavy chain variable region CDR3 comprising SEQ ID NO:9; a light chain variable region CDR1 comprising SEQ ID NO:10; a light chain variable region CDR2 comprising SEQ ID NO:11; and a light chain variable region CDR3 comprising SEQ ID NO:12.
ErbB3-binding IgG that downregulates ErbB3 on MALME-3M cells
An isolated full length IgG monoclonal antibody that binds to ErbB3 and downregulates the ErbB3 receptor in MALME-3M cells so that levels of ErbB3 on the surfaces of the cells are decreased by at least 50%, and comprises a heavy chain variable region sequence as set forth in SEQ ID NO:1 and a light chain variable region sequence as set forth in SEQ ID NO:2.
ErbB3-binding IgG that downregulates ErbB3 with specified CDR sequences
An isolated full length IgG monoclonal antibody that binds to ErbB3, downregulates the ErbB3 receptor in MALME-3M cells so that levels of ErbB3 on the surfaces of the cells are decreased by at least 50%, and comprises a heavy chain variable region CDR1 comprising SEQ ID NO:7; a heavy chain variable region CDR2 comprising SEQ ID NO:8; a heavy chain variable region CDR3 comprising SEQ ID NO:9; a light chain variable region CDR1 comprising SEQ ID NO:10; a light chain variable region CDR2 comprising SEQ ID NO:11; and a light chain variable region CDR3 comprising SEQ ID NO:12.
ErbB3-binding IgG with betacellulin phosphorylation potency (IC50 range)
An isolated full length IgG monoclonal antibody that binds to ErbB3, exhibits an IC50 for betacellulin mediated phosphorylation of ErbB3 that is from 5.32×10^-10 M to 1.32×10^-9 M in ADRr cells stimulated with betacellulin, and comprises a heavy chain variable region sequence as set forth in SEQ ID NO:1 and a light chain variable region sequence as set forth in SEQ ID NO:2.
ErbB3-binding IgG with betacellulin phosphorylation potency (IC50 range) defined by CDRs
An isolated full length IgG monoclonal antibody that binds to ErbB3, exhibits an IC50 for betacellulin mediated phosphorylation of ErbB3 that is from 5.32×10^-10 M to 1.32×10^-9 M in ADRr cells stimulated with betacellulin, and comprises a heavy chain variable region CDR1 comprising SEQ ID NO:7; a heavy chain variable region CDR2 comprising SEQ ID NO:8; a heavy chain variable region CDR3 comprising SEQ ID NO:9; a light chain variable region CDR1 comprising SEQ ID NO:10; a light chain variable region CDR2 comprising SEQ ID NO:11; and a light chain variable region CDR3 comprising SEQ ID NO:12.
ErbB3-binding IgG causing heregulin-mediated AKT phosphorylation decrease
An isolated full length IgG monoclonal antibody that binds to ErbB3, at a concentration of 63 nM causes a decrease in heregulin mediated phosphorylation of AKT of about 100% in MALME-3M cells, and comprises a heavy chain variable region sequence as set forth in SEQ ID NO:1 and a light chain variable region sequence as set forth in SEQ ID NO:2.
ErbB3-binding IgG causing heregulin-mediated AKT phosphorylation decrease defined by CDRs
An isolated full length IgG monoclonal antibody that binds to ErbB3, at a concentration of 63 nM causes a decrease in heregulin mediated phosphorylation of AKT of about 100% in MALME-3M cells, and comprises a heavy chain variable region CDR1 comprising SEQ ID NO:7; a heavy chain variable region CDR2 comprising SEQ ID NO:8; a heavy chain variable region CDR3 comprising SEQ ID NO:9; a light chain variable region CDR1 comprising SEQ ID NO:10; a light chain variable region CDR2 comprising SEQ ID NO:11; and a light chain variable region CDR3 comprising SEQ ID NO:12.
The claim set is directed to ErbB3-binding isolated full length IgG monoclonal antibodies that are constrained by defined heavy and light variable regions (SEQ ID NO:1 and SEQ ID NO:2) and/or by specific CDR sequences (SEQ ID NO:7 to SEQ ID NO:12), and further distinguished by functional criteria including ErbB3 downregulation on MALME-3M cell surfaces, betacellulin-mediated ErbB3 phosphorylation potency (IC50 range), and heregulin-mediated AKT phosphorylation decrease at a specified concentration.
Stated Advantages
Inhibits ErbB3 signaling relevant to cancers.
Decreases ErbB3 on the surfaces of MALME-3M cells by at least 50%.
Inhibits betacellulin mediated phosphorylation of ErbB3 with a specified IC50 range in ADRr cells.
Causes a decrease in heregulin mediated phosphorylation of AKT of about 100% in MALME-3M cells.
Reduces VEGF secretion and cell migration and reduces spheroid growth.
Inhibits tumor growth in xenograft models with dose-dependent effects.
Documented Applications
Treatment of cancers in which ErbB3 signaling is relevant (including functional tumor-growth inhibition in xenograft models).
Use in cellular contexts involving EGF-like ligand-mediated ErbB3 phosphorylation and downstream pathway activity (including betacellulin/ heregulin-related phosphorylation of ErbB3/AKT).
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