Targeting Diffuse Midline Glioma with a novel anti-CD99 Antibody

Balakrishnan, I.; Madhavan, K.; Pierce, A. M.; Michlin, J. A.; Brunt, B.; Chetty, S. L.; Wang, D.; DeSisto, J.; Nuss, Z.; Davidson, N.; Donson, A.; Jones, K.; Mitra, S. S.; Green, A.; Dahl, N.; Vibhakar, R.; Venkataraman, S.

doi:10.1101/2024.03.19.585814

bioRxiv · 10.1101/2024.03.19.585814

Targeting Diffuse Midline Glioma with a novel anti-CD99 Antibody

Balakrishnan, I.·Madhavan, K.·Pierce, A. M.·Michlin, J. A.·Brunt, B.·Chetty, S. L.·Wang, D.·DeSisto, J.·Nuss, Z.·Davidson, N.·Donson, A.·Jones, K.·Mitra, S. S.·Green, A.·Dahl, N.·Vibhakar, R.·Venkataraman, S.

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Abstract

Diffuse midline gliomas (DMGs) 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. We identified the cell surface antigen CD99 as notably expressed in DMGs, particularly in K27M+DMGs. We found that the increased expression of CD99 in K27M+DMGs was a result of the onco-histone K27M mutation. In K27M+DMG cells, CD99 inactivation impaired tumor growth by inducing cell differentiation, indicating an oncogenic role of CD99 enabled by blocking differentiation. We then developed a novel therapeutic anti-CD99 chimeric antibody, 10D1, with a membrane-proximal binding epitope, and evaluated its antitumor efficacy in preclinical models of K27M+DMG. 10D1 suppressed DMG growth in vitro and in vivo by inducing apoptosis. When combined with radiation treatment, 10D1 exhibited improved antitumor efficiency and xenograft survival, providing a strong justification for its clinical development as a therapy for DMGs. Statement of SignificanceThis study emphasizes that CD99 overexpression occurs due to the H3K27M mutation in Diffuse Midline Gliomas (DMGs). This heightened expression suppresses apoptosis, inhibits differentiation, and induces radio-resistance in DMGs. This research justifies using a novel CD99 antibody alone or combined with radiation therapy in human pediatric clinical trials.

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Balakrishnan, I., Madhavan, K., Pierce, A. M., Michlin, J. A., Brunt, B., Chetty, S. L., Wang, D., DeSisto, J., Nuss, Z., Davidson, N., Donson, A., Jones, K., Mitra, S. S., Green, A., Dahl, N., Vibhakar, R., Venkataraman, S.. 2024-03-21. Targeting Diffuse Midline Glioma with a novel anti-CD99 Antibody. https://doi.org/10.1101/2024.03.19.585814

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