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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