Antibodies against ERBB3 and uses thereof
Inventors
Schoeberl, Birgit • Nielsen, Ulrik • Feldhaus, Michael • Muruganandam, Arumugam • Buckler, David
Assignees
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Publication Number
US-8961966-B2
Publication Date
2015-02-24
Expiration Date
Abstract
The present invention provides a novel class of monoclonal antibodies which bind ErbB3 receptor and inhibits various ErbB3 functions. For example, the antibodies described herein are capable of binding to ErbB3 and inhibiting EGF-like ligand mediated phosphorylation of the receptor.
Core Innovation
The invention relates to a novel class of ErbB3-binding monoclonal antibodies that specifically bind ErbB3 and inhibit ErbB3 functions. The antibodies are defined by specific heavy chain variable region complementarity determining region sequences and light chain variable region complementarity determining region sequences, with SEQ ID NOs: 7, 8, and 9 for the heavy chain and SEQ ID NOs: 10, 11, and 12 for the light chain.
The disclosed antibodies inhibit EGF-like ligand mediated ErbB3 phosphorylation and heregulin-dependent signaling, including heregulin/epiregulin/epigen/biregulin signaling. They are associated with reduction of cell-surface ErbB3 via downregulation and internalization, and with inhibition of VEGF secretion, cell migration, and spheroid growth.
The document also provides binding and biophysical targeting information, including affinity measurements and epitope mapping to ErbB3 domain I and to residues 20–202, preferentially including residues 93–104. Antibody formats include human or humanized antibodies, fragments, multiple isotypes, bispecific antibodies, and immunoconjugates, together with pharmaceutical compositions and diagnostic or prognostic uses via ErbB3 binding on patient cells.
Claims Coverage
The claim coverage centers on isolated monoclonal antibodies or antigen-binding portions thereof that specifically bind ErbB3 and are defined by specific heavy- and light-chain sequence IDs. Across the independent claims, four inventive features are present.
ErbB3-specific antibody defined by heavy and light CDR sequence IDs
An isolated monoclonal antibody or antigen binding portion that specifically binds to ErbB3 and comprises heavy chain variable region CDR1, CDR2, and CDR3 amino acid sequences as set forth in SEQ ID NOs: 7, 8, and 9, respectively, and light chain variable region CDR1, CDR2, and CDR3 amino acid sequences as set forth in SEQ ID NOs: 10, 11, and 12, respectively.
ErbB3-specific antibody defined by heavy and light variable region sequence IDs
An isolated monoclonal antibody or antigen binding portion that specifically binds to ErbB3 and comprises heavy and light chain variable regions as set forth in SEQ ID NOs: 1 and 2, respectively.
Defined binding affinity for ErbB3
A monoclonal antibody or its antigen binding portion that binds to ErbB3 with an affinity of 10^7 to 10^10 M^-1 as measured by surface plasmon resonance or a cell binding assay.
Functional inhibition of ErbB3 receptor activity
A monoclonal antibody or its antigen binding portion that downregulates the ErbB3 receptor on MALME-3M cells, with downregulation measured by FACS analysis, and inhibits VEGF secretion by heregulin-stimulated MCF-7 cells.
The core coverage is directed to ErbB3-specific isolated monoclonal antibodies whose specificity is defined by particular sequence IDs for CDRs or for heavy and light variable regions, together with binding-affinity and functional activity limitations.
Stated Advantages
ErbB3 downregulation and inhibition of ErbB3-dependent cellular responses.
Inhibition of proliferation of ErbB3-expressing tumor cells.
Inhibition of migration and multicellular tumor spheroid growth.
Inhibition of ErbB3 phosphorylation triggered by heregulin and betacellulin.
Suppression of downstream AKT phosphorylation.
Inhibition of heregulin binding to ErbB3.
Reduction of VEGF secretion and angiogenesis-related effects.
Inhibits EGF-like ligand mediated ErbB3 phosphorylation.
Inhibits heregulin/epiregulin/epigen/biregulin signaling.
Reduces cell-surface ErbB3 via downregulation and internalization.
Suppresses xenograft tumor growth.
Provides broad functional activity compared with agents such as cetuximab, lapatinib, and pertuzumab.
Documented Applications
ADRr xenografts.
ErbB3-expressing tumor cells.
MALME-3M cells.
MCF-7 cells.
Therapeutic use in cancers, including contexts involving KRAS mutation and PI3K mutation.
Combination therapy with anti-cancer agents including erlotinib, paclitaxel, and cisplatin.
Diagnostic or prognostic use via ErbB3 binding on patient cells.
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