Clinical Cancer Research: The B7-H3-targeting antibody-drug conjugate m276-SL-PBD is potently effective against pediatric cancer preclinical solid tumor models

Nathan M. KendserskyJarrett M LindsayEdward A. KolbMalcolm A. SmithBeverly A. TeicherStephen EricksonEric J EarleyYaël P. MosséDaniel MartinezJennifer PogorilerKateryna KrytskaKhushbu PatelDavid GroffMatthew TsangSamson GhiluYifei WangSteven SeamanYang FengBrad St. CroixRichard GorlickRaushan T. KurmashevaPeter J. Houghton and John M. Maris

Abstract

Purpose: Patients with relapsed pediatric solid malignancies have few therapeutic options, and many of these patients die of their disease. B7-H3 is an immune checkpoint protein encoded by the CD276 gene that is overexpressed in many pediatric cancers. Here, we investigate the activity of the B7-H3-targeting antibody-drug conjugate (ADC) m276-SL-PBD in pediatric solid malignancy patient-derived and cell line-derived xenograft (PDX and CDX) models. Experimental Design: B7-H3 expression was quantified by RNA sequencing and by immunohistochemistry on pediatric PDX microarrays. We tested the safety and efficacy of m276-SL-PBD in two stages. Randomized trials of m276-SL-PBD of 0.5mg/kg on days 1, 8, and 15 compared to the vehicle were performed in PDX or CDX models of Ewing sarcoma (N=3), rhabdomyosarcoma (N=4), Wilms tumors (N=2), osteosarcoma (N=5) and neuroblastoma (N=12). We then performed a single mouse trial (SMT) in 47 PDX or CDX models using a single 0.5 m/kg dose of m276-SL-PBD. Results: The vast majority of PDX and CDX samples studied showed intense membranous B7-H3 expression (median H-score 177, SD 52). In the randomized trials, m276-SL-PBD showed a 92.3% response rate, with 61.5% of models showing a maintained complete response (MCR). These data were confirmed in the single mouse trial with an overall response rate of 91.5% and an MCR rate of 64.4%. The treatment-related mortality rate was 5.5% with late weight loss observed in a subset of models dosed weekly x 3. Conclusions: m276-SL-PBD has significant anti-tumor activity across a broad panel of pediatric solid tumor PDX models.

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Since 2004, UT Health San Antonio, Greehey Children’s Cancer Research Institute’s (Greehey CCRI) mission has been to advance scientific knowledge relevant to childhood cancer, contribute to understanding its causes, and accelerate the translation of knowledge into novel therapies. Greehey CCRI strives to have a national and global impact on childhood cancer by discovering, developing, and disseminating new scientific knowledge. Our mission consists of three key areas — research, clinical, and education.

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