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-9487588-B2
Publication Date
2016-11-08
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 anti-ErbB3 antibodies that bind the ectodomain of human ErbB3 and include defined heavy chain variable region and light chain variable region sequence requirements. The antibodies comprise specified residues of SEQ ID NO:1 and SEQ ID NO:2, or amino acid sequences at least 90% identical thereto, and are described as having functional anti-tumor activity and signaling inhibition associated with biomarkers and mutations.
The document addresses diagnosing and treating ErbB3-dependent cancers by using ErbB3-binding antibodies in combination with tumor-sample testing. It describes testing based on pErbB3 thresholds to decide whether to administer an anti-ErbB3 antibody, linking biomarker status to treatment selection for ErbB3-dependent cancer.
Mechanistically, the document describes inhibition of ErbB3 phosphorylation and ErbB3 signaling, including effects on downstream signaling such as AKT phosphorylation. It also describes effects consistent with ErbB3 downregulation and functional inhibition outcomes such as reduced proliferation, reduced migration, reduced spheroid growth, and in vivo xenograft tumor growth inhibition.
Claims Coverage
The consolidated claim coverage includes one independent claim defining an anti-ErbB3 antibody with specific heavy- and light-chain variable region sequence and residue requirements, and binding to the ectodomain of human ErbB3. Dependent claims refine isotype, sequence identity threshold, and a pharmaceutical composition formulation.
Ectodomain-binding anti-ErbB3 antibody with defined variable-region sequences and residues
An anti-ErbB3 antibody comprising a heavy chain variable region comprising SEQ ID NO:1, or an amino acid sequence at least 90% identical thereto, and a light chain variable region comprising SEQ ID NO:2, or an amino acid sequence at least 90% identical thereto, wherein the antibody binds the ectodomain of human ErbB3, and wherein the antibody comprises variable heavy chain residues Tyr32 or Phe32, Va133, Trp57, Met102, Thr104, and Ile105 of SEQ ID NO:1, and variable light chain residues Asp28, Tyr32 or Phe32, and Tyr93 or Phe93 of SEQ ID NO:2.
IgG2 isotype anti-ErbB3 antibody
The antibody of the anti-ErbB3 antibody feature of the independent claim is specified to be an IgG2 isotype antibody.
High-identity variable-region anti-ErbB3 antibody
An anti-ErbB3 antibody whose heavy- and light-chain variable regions contain amino acid sequences that are at least 95% identical to SEQ ID NO:1 and SEQ ID NO:2, respectively.
Pharmaceutical composition formulation
A pharmaceutical composition that includes the antibody of the anti-ErbB3 antibody feature of the independent claim formulated in a pharmaceutically acceptable carrier.
Overall, the claim coverage centers on an ectodomain-binding anti-ErbB3 antibody defined by specific SEQ ID NO:1/SEQ ID NO:2 variable-region sequence and residue requirements, with refinements to IgG2 isotype, a higher 95% identity threshold, and formulation as a pharmaceutical composition in a pharmaceutically acceptable carrier.
Stated Advantages
Functional anti-tumor activity.
Signaling inhibition.
Inhibition of ErbB3 phosphorylation and ErbB3 signaling, including downstream AKT phosphorylation.
Reduced proliferation, reduced migration, and reduced spheroid growth.
In vivo xenograft tumor growth inhibition.
Documented Applications
Therapeutic methods for ErbB3-associated cancers, including cancers in KRAS- and PI3K-mutant contexts.
Diagnostic methods for ErbB3-associated cancers.
Kits for diagnosing and treating ErbB3-associated cancers.
Diagnosing and treating ErbB3-dependent cancers by using ErbB3-binding antibodies in combination with tumor-sample testing based on pErbB3 thresholds.
Administration of anti-ErbB3 antibodies in pharmaceutical formulations through oral, nasal, topical, rectal, vaginal, and parenteral routes.
Optional BBB-crossing liposome formulations for antibody administration.
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