Co-use of a clusterin inhibitor with an EGFR inhibitor to treat cancer
Inventors
Tremblay, Gilles Bernard • Viau, Elisabeth • Filion, Mario
Assignees
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Publication Number
US-9822170-B2
Publication Date
2017-11-21
Expiration Date
Abstract
Epidermal growth factor receptor (EGFR) expression and phosphorylation is increased in cancer cells treated with anti-clusterin antibodies. Such treatment is also accompanied with the reappearance of an epithelial phenotype of the cancer cell, as determined by an increased E-cadherin expression at the surface of cancer cells. Clusterin inhibitors may thus induce reversal of the epithelial to mesenchymal phenotype and restore sensitivity of cancer cells to EGFR inhibitors. Combinations of a clusterin inhibitor and an EGFR as well as their use in treatment of cancer are thus provided herewith.
Core Innovation
The invention relates to a combination cancer therapy that administers an anti-clusterin antibody, or an antigen binding fragment thereof, that binds to human clusterin amino acids 421 to 443 and is capable of inhibiting epithelial-to-mesenchymal transition (EMT). This anti-clusterin agent is administered together with an epidermal growth factor receptor (EGFR) inhibitor to an individual having or suspected of having carcinoma. The approach targets EMT in order to coordinate the anti-carcinoma effects with EGFR inhibition.
The background problem addressed is carcinoma treatment in which resistance to EGFR inhibitor therapy is implicated, and EMT is associated with carcinoma progression and altered epithelial/mesenchymal phenotypes. The therapy aims to reverse EMT and re-sensitize tumors to EGFR blockade when an EGFR tyrosine kinase inhibitor is used. In the provided description, the anti-clusterin antibody increases epithelial marker E-cadherin and elevates EGFR expression and EGFR tyrosine phosphorylation in NSCLC cell lines.
The documented combination is exemplified by using an anti-sCLU antibody such as h16B5 in combination with an EGFR inhibitor such as erlotinib, and also references other EGFR tyrosine kinase inhibitors. The described results indicate that adding h16B5 enhances the anti-tumor effects of erlotinib, including in more resistant cells. The scope includes carcinoma indications and EMT/marker-related readouts used to support the treatment rationale.
Claims Coverage
The document provides two independent methods that share the same core combination: an anti-clusterin antibody that binds human clusterin amino acids 421 to 443 and is capable of inhibiting EMT, administered with an EGFR tyrosine kinase inhibitor selected from a defined group. The independent claims differ mainly in the treatment endpoint language while maintaining the same combinatorial structure and cancer scope.
Anti-clusterin antibody binding human clusterin 421 to 443 and inhibiting EMT with EGFR inhibitor
Administering an anti-clusterin antibody or an antigen binding fragment thereof that binds amino acids 421 to 443 of human clusterin and is capable of inhibiting epithelial-to-mesenchymal transition (EMT) together with an epidermal growth factor receptor (EGFR) inhibitor to an individual having or suspected of having specified carcinomas.
EGFR tyrosine kinase inhibitor selection from a defined group
The EGFR inhibitor is an EGFR tyrosine kinase inhibitor selected from the group consisting of gefitinib, erlotinib, imatinib, lapatinib or semazinib.
Carcinoma treatment across specified cancer types
The anti-clusterin antibody and EGFR inhibitor combination is administered to an individual having or suspected of having breast carcinoma, prostate carcinoma, colorectal carcinoma, head and neck carcinoma, lung carcinoma, pancreatic cancer or renal cell carcinoma.
Reducing growth of carcinoma cells using anti-clusterin antibody plus EGFR inhibitor
Reducing the growth of carcinoma cells by administering an anti-clusterin antibody or antigen binding fragment that binds amino acids 421 to 443 of human clusterin and is capable of inhibiting EMT together with an EGFR inhibitor to an individual having or suspected of having the specified carcinoma types.
Across the independent claims, the inventive coverage is anchored in the combination of an EMT-inhibiting anti-clusterin antibody that binds human clusterin amino acids 421 to 443 with a defined EGFR tyrosine kinase inhibitor group, applied to a specified list of carcinoma indications.
Stated Advantages
Re-sensitize tumors to EGFR blockade by reversing EMT.
Enhance the anti-tumor effect of erlotinib, including in more resistant cells.
Documented Applications
Combination cancer therapy for carcinoma, including treatment or reducing growth of carcinoma cells in breast carcinoma, prostate carcinoma, colorectal carcinoma, head and neck carcinoma, lung carcinoma, pancreatic cancer, and renal cell carcinoma.
NSCLC settings where h16B5 increases E-cadherin and elevates EGFR expression and EGFR tyrosine phosphorylation, and where adding h16B5 enhances erlotinib anti-tumor effects.
Breast carcinoma subtypes including triple negative breast cancer and basal-like breast cancer.
Lung carcinoma narrowed to non-small cell lung cancer.
Metastatic carcinoma context.
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