EXTH-49. A NOVEL THERAPEUTIC ANTIBODY TARGETING DIFFUSE MIDLINE GLIOMA

There is an unmet need to identify novel targeted therapies for H3K27M mutated Diffuse Midline Gliomas. (DMG) Using genetic overexpression and deletion of H3K27M in model cells we identified high expression of CD99 mRNA in H3K27M-mutant expressing DIPGs compared to other normal brain counterparts. A cell surface antigen screen confirmed that CD99 was highly expressed in DMG compared to normal tissues. We then developed a novel chimeric CD99 antibody based on a human IgG4 scaffold and tested the anti-tumor efficacy of this antibody in vitro and in vivo DMG xenografts. Our new CD99 antibody (10D1) significantly reduced DIPG tumor cell proliferation in vitro. In vivo intravenous administration of the antibody in orthotopic DMG tumor bearing mice showed complete clearance of tumor with prolonged animal survival establishing anti-tumor efficacy of 10D1 and demonstrating its ability in crossing the blood-brain-pons barrier. Loco-regional administration of 10D1, intratumorally or to the lateral ventricle, showed similar anti-tumor effects at reduced antibody concentrations while limiting systemic effects on normal T cells. 10D1 combined with radiation to further prolong the survival of orthotopic xenograft-bearing animals. In conclusion, we have identified a novel therapeutic for DMG which is now in further development.