Details

Autor(en) / Beteiligte

• Kendsersky, Nathan M
• Lindsay, Jarrett
• Kolb, E Anders
• Smith, Malcolm A
• Teicher, Beverly A
• Erickson, Stephen W
• Earley, Eric J
• Mosse, Yael P
• Martinez, Daniel
• Pogoriler, Jennifer
• Krytska, Kateryna
• Patel, Khushbu
• Groff, David
• Tsang, Matthew
• Ghilu, Samson
• Wang, Yifei
• Seaman, Steven
• Feng, Yang
• Croix, Brad St
• Gorlick, Richard
• Kurmasheva, Raushan
• Houghton, Peter J
• Maris, John M

Titel

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

Ist Teil von

• Clinical cancer research, 2021-05, Vol.27 (10), p.2938-2946

Ort / Verlag

United States

Erscheinungsjahr

2021

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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 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. 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 ( = 3), rhabdomyosarcoma ( = 4), Wilms tumors ( = 2), osteosarcoma ( = 5), and neuroblastoma ( = 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. 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. m276-SL-PBD has significant antitumor activity across a broad panel of pediatric solid tumor PDX models.