Data from The B7-H3–Targeting Antibody–Drug Conjugate m276-SL-PBD Is Potently Effective Against Pediatric Cancer Preclinical Solid Tumor Models

Abstract

<div>AbstractPurpose:<p>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 <i>CD276</i> 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 (PDX) and cell line–derived xenograft (CDX) models.</p>Experimental Design:<p>B7-H3 expression was quantified by RNA sequencing and by IHC on pediatric PDX microarrays. We tested the safety and efficacy of m276-SL-PBD in two stages. Randomized trials of m276-SL-PBD of 0.5 mg/kg on days 1, 8, and 15 compared with vehicle were performed in PDX or CDX models of Ewing sarcoma (<i>N</i> = 3), rhabdomyosarcoma (<i>N</i> = 4), Wilms tumors (<i>N</i> = 2), osteosarcoma (<i>N</i> = 5), and neuroblastoma (<i>N</i> = 12). We then performed a single mouse trial in 47 PDX or CDX models using a single 0.5 m/kg dose of m276-SL-PBD.</p>Results:<p>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 MCR rate of 64.4%. Treatment-related mortality rate was 5.5% with late weight loss observed in a subset of models dosed once a week for 3 weeks.</p>Conclusions:<p>m276-SL-PBD has significant antitumor activity across a broad panel of pediatric solid tumor PDX models.</p></div>