Chimeric antigen receptor modified immune cells recognizing DKK/HLA-A2 complex for cancer immunotherapy

Description of Invention

The invention is a chimeric antigen receptor T cell therapy directed against solid tumors expressing the Dickkopf (Dkks) protein.. The Dickkopf family (Dkks) is a canonical Wnt signaling pathway antagonist which plays varied roles in human physiology and as well as assuming a central role in bone development and formation. As cancer cells, but not normal cells, express on their surface DKK-I peptides/HLA-A2 molecules in HLA-A2+ cancer patients, the inventors synthesized the DKKI peptide P20/HLA-A2 and used it to immunized mice in order to obtain monoclonal antibodies (mAbs) that bind specifically with DKKI-expressing, HLA-A2+ human cancer cells but not HLA-A2+ blood cells or normal tissue cells. The coding sequence of this mAb was used to construct CAR-T DKK1-A2, the construct that can be transduced to express a chimeric antigen receptor (CAR). The immune cells engineered in vitro by expressed CAR molecular that exhibits a specific and powerful anti-tumor cellular immune activity in vitro and in vivo. CAR-T DKK1-A2 cells specifically recognize with DKK1- HLA-A2+ expressed on the human cancer cells surface but not HLA-A2+ blood cells or normal tissue cells and trigger cell-mediated cytotoxicity.

 

Stage of Development

In vivo data: The inventors are currently conducting in vivo studies in xenografted mouse models against a variety of solid tumors and have demonstrated that this specific CAR-T kills cancer cells in vitro and in vivo xenografted mouse models.

 

Competitive Landscape

A number of CAR-T therapies are in development against solid tumors.  However, none of these therapies are directed against DKK-1. There remains ample opportunity for developers to explore other targets in solid tumors, as CAR cell development in these settings is relatively novel, and relatively few therapies are being developed.

 

Competitive Advantages

DKK1 is broadly overexpressed by tumor cells including hematological malignancies and solid tumors but absent from most normal tissues, may be an ideal target for immunotherapy.

• Therapeutic antibody and CAR-T cells to target DKK1 for cancer immunotherapy have been developed and demonstrated that these specific antibodies and CAR-T cells can kill cancer cells in vitro and in vivo xenografted mouse models.

• VEGF and HER2 are overexpressed in limited cancers. Clinical studies showed that currently approved VEGF-targeting therapies produce initial responses that are followed by a restoration of tumor growth and progression.

 

Patent Information:
Licensing Contact
Joe Jilka
jjilka@houstonmethodist.org

Inventors:
Qing Yi
Jianfei Qian
Wei Xiong