Description

Folate receptor alpha as a therapeutic target in breast carcinomas using recombinant antibodies

Anthony Cheung, James Opzoomer, Kristina Ilieva, Patrycja Gazinska, Hasan Mirza, Matthew Fittall, Rebecca Marlow, Anita Grigoriadis, Andrew Tutt and Sophia Karagiannis

King's College London, St. John's Institute of Dermatology, Division of Genetics & Molecular Med, London, UK

Triple negative breast carcinomas are aggressive tumors for which no targeted therapies are available. Recent developments have identified the tumor-associated antigen Folate Receptor α (FRα), a cell surface protein known to mediate intracellular transport of folate, as a target for antibody therapies. We therefore aimed to derive a better understanding of the clinical relevance of FRα and its role in cancer progression, and to identify new treatment strategies against FRα-expressing cancer cell clearance with monoclonal antibodies.

Methods: FRα expression patterns were examined by transcriptomic analyses using breast carcinoma samples, or by flow cytometry screening of established cell lines. RNA interference was used to deplete FRα expression for in vitro functional studies. The tumor cell killing effects of FRα-targeting antibodies in the presence of human immune effector cells were measured by a multicolour flow cytometry-based assay and in humanized xenograft model.

Results: Elevated FRα expression in basal compared to other breast carcinoma subtypes was demonstrated in the King’s College London sample collection (N=155) and confirmed by interrogating the METABRIC database (N=1548). Knockdown of FRα led to reduction in cellular proliferation, colony formation and activation of downstream signalling pathway molecules. We demonstrated the ability of an antibody clone raised against FRα to engender cytotoxic and phagocytic mechanisms to eradicate breast cancer cells by activating healthy volunteer and patient peripheral blood mononuclear cells. Subsequently we demonstrated human immune cell engraftment and reduction of tumor volumes with antibody treatments in human orthotropic xenograft-bearing mice.

Conclusions: Our results provide novel perspectives on the expression and function of FRα, and we identify the potential tumor restricting properties of monoclonal antibody-based targeted therapies.