Development of an Anti-CD99 Antibody Enables Targeting of Diffuse Midline Glioma.
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UNLABELLED: Diffuse midline gliomas (DMG) are devastating brain tumors that occur primarily in children. The salient feature of these tumors is the presence of a H3K27M mutation (K27M), associated with the worst prognosis. Development of effective strategies for treating K27M+ DMG is desperately needed to help improve patient outcomes. In this study, we identified the cell surface antigen CD99 as notably expressed in DMGs, particularly in K27M+ DMGs. The increased expression of CD99 in K27M+ DMGs was a result of the oncohistone K27M mutation. In K27M+ DMG cells, CD99 inactivation impaired tumor growth by inducing cell differentiation. The development of a therapeutic anti-CD99 chimeric antibody, 10D1, with a membrane-proximal binding epitope enabled the evaluation of the antitumor efficacy of targeting CD99 in preclinical models of K27M+ DMGs. 10D1 suppressed DMG growth in vitro and in vivo by inducing apoptosis. When combined with radiation treatment, 10D1 exhibited improved antitumor efficacy and prolonged xenograft survival. Together, these findings provide a strong justification for the clinical development of 10D1 as a therapy for targeting CD99 to treat DMGs. SIGNIFICANCE: The H3K27M mutation in diffuse midline glioma increases CD99 expression to suppress apoptosis, inhibit differentiation, and induce radioresistance, supporting using the anti-CD99 antibody 10D1 in pediatric brain cancer trials.