Antibodies against the ectodomain of ErbB3 and uses thereof
Inventors
Schoeberl, Birgit • Nielsen, Ulrik • Feldhaus, Michael • Muruganandam, Arumugam • Buckler, David
Assignees
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Publication Number
US-8691225-B2
Publication Date
2014-04-08
Expiration Date
Abstract
The present invention provides a novel class of antibodies and antigen binding fragments thereof that bind the extracellular domain of ErbB3 receptor and inhibit various ErbB3 functions. For example, the antibodies and antigen binding fragments described herein are capable of binding to the receptor designated ErbB3 and inhibiting EGF-like ligand mediated phosphorylation of the receptor. Such antibodies and antigen binding fragments thereof have the useful characteristic of inhibiting the proliferation of cancer cells expressing ErbB3.
Core Innovation
The invention relates to fully human, humanized, or chimeric anti-ErbB3 antibodies and antigen-binding fragments that bind ErbB3, in particular Domain I of ErbB3. The antibodies are defined by specific heavy-chain and light-chain variable region CDR sequence identities and are described with binding and epitope characteristics, including inhibition of EGF-like ligand-mediated ErbB3 phosphorylation. The invention also relates to pharmaceutical formulations and administration routes for anti-ErbB3 antibodies and antigen-binding portions, together with methods of using such antibodies in a human subject.
ErbB3 is expressed in cancers and is activated by EGF-like ligands, leading to phosphorylation of ErbB3 and downstream tumor behaviors. By binding Domain I and inhibiting ligand-mediated phosphorylation of ErbB3, the antibodies downregulate cell-surface ErbB3 and interfere with ErbB3-driven phenotypes. Functional outcomes described include proliferation inhibition, inhibition of VEGF secretion, inhibition of cell migration, and inhibition of spheroid growth.
The invention further provides diagnostic and therapy-decision use of ErbB3 biology. It describes measuring ErbB3 binding and/or upregulation and using tumor phospho-ErbB3 (pErbB3) relative to an ACHN-cell culture threshold to determine whether to include the anti-ErbB3 antibody in therapy. The document also describes therapeutic and diagnostic contexts involving ErbB3-associated cancers and measurement of antibody binding or pErbB3.
Claims Coverage
The provided claim content contains one independent claim directed to a treatment method using a monoclonal antibody with specified heavy- and light-chain CDR sequence IDs. The inventive coverage centers on the antibody’s binding specificity to human ErbB3 and the CDR sequence requirements, with dependent claims adding functional and contextual refinements.
Treating an ErbB3-expressing cancer with a specified CDR-defined monoclonal antibody
A method of treating an ErbB3-expressing cancer in a human subject by administering a therapeutically effective amount of a monoclonal antibody or antigen binding portion thereof that binds human ErbB3 and that 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 core claim coverage is a treatment method for ErbB3-expressing cancers in humans using an ErbB3-binding monoclonal antibody or antigen-binding portion with specified heavy- and light-chain CDR sequence IDs. The claim set is further associated with inhibition of ligand-mediated ErbB3 phosphorylation and with tumor-type and combination-therapy refinements.
Stated Advantages
Inhibits betacellulin, heregulin, or TGFα-mediated phosphorylation of ErbB3 in AdrR cells.
Suppresses ErbB3-driven tumor behaviors, including downregulating cell-surface ErbB3, inhibiting VEGF secretion, inhibiting cell migration, and inhibiting spheroid growth.
Provides proliferation inhibition associated with ErbB3 pathway suppression.
Suppresses ErbB3 signaling including AKT.
Downregulates ErbB3 in vitro and in vivo and inhibits tumor cell proliferation and tumor growth in xenograft models.
Documented Applications
Treatment of an ErbB3-expressing cancer in a human subject using a specified monoclonal antibody or antigen binding portion thereof.
Treatment context includes tumors selected from ovarian, pancreatic, renal, prostate, lung, melanoma, or breast cancer.
Diagnostic/prognostic use cases are described as measuring antibody binding or pErbB3.
Diagnostic use by measuring ErbB3 binding and/or upregulation and using tumor phospho-ErbB3 (pErbB3) relative to an ACHN-cell culture threshold to guide whether to include anti-ErbB3 antibody therapy.
Combination therapy in treating cancer by combining the anti-ErbB3 antibody with agents including erlotinib, paclitaxel, and cisplatin.
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