Compositions and methods for restoring sensitivity to treatment with HER2 antagonists
Inventors
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-7674460-B2
Publication Date
2010-03-09
Expiration Date
Abstract
Methods and compositions for restoring growth inhibition sensitivity to a tumor cell resistant to growth inhibition by HER2 antagonists. The methods involve administering a PCDGF antagonist to the cell in an amount effective to stimulate or restore growth inhibition sensitivity to HER2 antagonists. The invention also provides treatment regimens, and therapeutic compositions comprising an HER2 antagonist and a PCDGF antagonist.
Core Innovation
The patent describes that the autocrine growth factor PCDGF, also known as GP88/GEP/progranulin family, confers resistance to HER2 antagonists in HER2-overexpressing tumor cells, including trastuzumab (Herceptin®). It addresses HER2-antagonist resistance mediated by PCDGF and states therapeutic strategies to restore HER2-antagonist sensitivity by administering a PCDGF antagonist, including anti-PCDGF neutralizing antibodies, antibodies binding PCDGF or its receptor, and nucleic acid-based antagonists such as antisense/siRNA, either alone or together with an HER2 antagonist.
The patent further provides diagnostic guidance based on detecting elevated PCDGF in patient samples. It describes expected pharmacodynamic outcomes including reduction in c-erbB2 phosphorylation and increased HER2-antagonist sensitivity, and it includes experimental evidence supporting PCDGF-driven HER2-antagonist resistance and restoration via pathway targeting.
Claims Coverage
The patent provides coverage through two independent claims directed to a combined pharmaceutical composition and a kit. Across the independent claims, the inventive focus includes combining an HER2 antagonist with a PCDGF antagonist, with the PCDGF antagonist specified as an anti-PCDGF antibody produced from a defined set of hybridoma cell lines or antigen-binding fragments.
Combined HER2 antagonist and PCDGF antagonist pharmaceutical composition
A pharmaceutical composition comprising a pharmaceutically effective amount of an HER2 antagonist, where the HER2 antagonist is a HER2 antibody or an antigen-binding fragment thereof, and a pharmaceutically effective amount of PCDGF antagonist, where the PCDGF antagonist is an anti-PCDGF antibody produced from a hybridoma cell line selected from the group consisting of 6B3, 6B2, 6C12, 5B4, 5G6, 4D1, 3F8, 3F5, 3F4, 3G2, 4F10, and 2A5 hybridoma cell lines, or an antigen-binding fragment thereof.
Kit with HER2 antagonist and anti-PCDGF antibody
A kit comprising a container containing an HER2 antagonist or a pharmaceutically acceptable salt thereof and a container containing an anti-PCDGF antibody or an antigen-binding fragment produced from a hybridoma cell line selected from the group consisting of 6B3, 6B2, 6C12, 5B4, 5G6, 4D1, 3F8, 3F5, 3F4, 3G2, 4F10, and 2A5 hybridoma cell lines.
Overall, the claims cover therapeutic formulations and packaged products that combine an HER2 antagonist with a PCDGF antagonist, where the PCDGF antagonist is an anti-PCDGF antibody produced from specified hybridoma cell lines or antigen-binding fragments.
Stated Advantages
Restore HER2-antagonist sensitivity in HER2-overexpressing tumor cells that exhibit PCDGF-mediated resistance.
Reduction in c-erbB2 phosphorylation.
Increased HER2-antagonist sensitivity.
Documented Applications
Therapeutic strategies for HER2-antagonist resistance in HER2-overexpressing tumor cells mediated by PCDGF, including administration of a PCDGF antagonist with or without an HER2 antagonist.
Diagnostic guidance based on detecting elevated PCDGF in patient samples.
Interested in licensing this patent?