Development of an Anti-CD99 Antibody Enables Targeting of Diffuse Midline Glioma

IF 16.6 1区 医学 Q1 ONCOLOGY
Ilango Balakrishnan, Krishna Madhavan, Angela Pierce, Joshua Michlin, Breauna Brunt, Senthilnath Lakshmanachetty, Dong Wang, John DeSisto, Zachary James. Nuss, Nathan Davidson, Faye Walker, Ammu Suresh, Andrew Donson, Bridget Sanford, Kenneth L. Jones, Etienne P. Danis, Siddhartha S. Mitra, Adam L. Green, Nathan Dahl, Rajeev Vibhakar, Sujatha Venkataraman
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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. Development of effective strategies for treating K27M+ DMG is desperately needed to help improve patient outcomes. Here, 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 onco-histone 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+ DMG. 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.
一种靶向弥漫性中线胶质瘤的抗cd99抗体的开发
弥漫性中线胶质瘤(dmg)是一种主要发生于儿童的破坏性脑肿瘤。这些肿瘤的显著特征是存在H3K27M突变(K27M),与最差的预后相关。迫切需要开发治疗K27M+ DMG的有效策略,以帮助改善患者的预后。在这里,我们发现细胞表面抗原CD99在DMGs中显著表达,特别是在K27M+ DMGs中。CD99在K27M+ dmg中的表达增加是肿瘤组蛋白K27M突变的结果。在K27M+ DMG细胞中,CD99失活通过诱导细胞分化来抑制肿瘤生长。具有膜-近端结合表位的治疗性抗CD99嵌合抗体10D1的开发,能够在K27M+ DMG的临床前模型中评估靶向CD99的抗肿瘤效果。10D1通过诱导细胞凋亡抑制DMG体外和体内生长。当与放射治疗联合时,10D1表现出更好的抗肿瘤疗效和延长异种移植物的生存时间。总之,这些发现为临床开发10D1作为靶向CD99治疗dmg的疗法提供了强有力的理由。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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