Cancer stem-cell therapy with anti-ganglioside humanized monoclonal antibodies – GANGSTEMAB

Based on experimental evidence, scientists have proposed that tumors may possess cells similar in phenotype to normal stem cells and that these cancer stem cells (CSCs) are the origin of tumors. Cancer stem cells (CSCs) theory supposes the existence of some highly tumorigenic cells with the properties of normal stem cells, i.e. capable to give raise - in asymmetric division - to cancer cells. Biochemical and biological characterization of these small populations of cancer initiating cells implicated their critical roles in cancer initiation, cancer progression, and malignancy.
In our consortium, we have generated the mouse mAb, namely 8B6, which is specific to the O-acetylated derivative of GD2: O-acetyl-GD2 ganglioside (OAcGD2). This specific antibody shows no cross reaction with GD2 or other O-acetyl-gangliosides. OAcGD2 is not expressed at the surface of the nerves contrary to GD2 ganglioside, however, it is expressed at comparable levels on tumor cells (up to 106 sites/cell) (Alvarez-Rueda et al. 2011). The GD2 ganglioside has been recently identified as a human neural stem cell surface marker. In recent studies, Battula et al. reported that following the induction of epithelial-to-mesenchymental transition, human mammary epithelial cells show functional properties similar to those of human bone marrow-derived mesenchymental stem cells. Therefore, they hypothesized that the cell markers expressed on the surface of MSCs could also be expressed on the surface of breast CSCs, and they recently confirmed that GD2 identifies breast stem cells.
These recent data prompted us to define the expression profile of OAcGD2 in glioblastoma (GBM) and breast cancers and to evaluate the distribution of OAcGD2 in cancer non-stem and stem cells, in order to determine if OAcGD2 could be a reliable surface marker for both pathologies.
The aim of our GANGSTEMAB research program is to validate the clinical potential of anti-OAcGD2 mAbs for targeting cancer stem cells in the treatment of two cancers: GBM and breast cancer. Our objectives are:
The relationship between OAcGD2 expression and the “stem-ness” of cancer cells will be explored.
In glioma, OAcGD2 phenotype will be related to existing CSC biomarkers and oncogenic properties.
In breast cancer, OAcGD2 phenotype and oncogenic properties will be studied within enriched CSC populations.
OAcGD2 phenotype will be studied before and after therapies known to enriched CSC within tumors.
OAcGD2 chimeric mAb therapy efficacy will be studied in cellular and animal models, alone or in combination with existing therapies.
OAcGD2 mAb wil be humanized to allow repeated injections for allowing repeated or adjuvant treatments.
The innovative potential of mAb anti-OAcGD2 lies in the specific expression of the antigen OAcGD2 in CSCs of glioblastoma and in breast cancers and probably other cancers (patent being filed). Moreover, compared to anti-GD2 mAbs, anti-OAcGD2 mabs do not bind to peripheral nerves and thus do not induce pain (patent granted in Europe, pending in other countries). Besides, OAcGD2 chimeric antibodies with improved cytotoxic properties have been developed and are being patented by Partners 1 and 2.
If we succeed to prove the concept of CSC targeting using OAcGD2 for these two diseases, it can be extended to other cancers.
However to reach this objective, we will have to overcome the following challenges:
• CSC are not precisely defined;
• Animal models of CSC therapy might be far from clinical situations;
• The expression of OAcGD2 in CSCs must be checked, especially after or during chemotherapy and radiotherapy;
• The affinity, the specificity and the cytotoxicity of the humanized version of mAb 8B6 must be kept.

If we succeed to prove the potential value of this antibody in glioma and/or breast cancer, it might become a therapeutic option also in other CSC-dependent cancers as leukemia, colon cancer, head and neck, pancreas, etc.