TY - JOUR
T1 - The B7-H3–targeting antibody–Drug conjugate m276-SL-PBD is potently effective against pediatric cancer preclinical solid tumor models
AU - Kendsersky, Nathan M.
AU - Lindsay, Jarrett
AU - Anders Kolb, E.
AU - Smith, Malcolm A.
AU - Teicher, Beverly A.
AU - Erickson, Stephen W.
AU - Earley, Eric J.
AU - Mosse, Yael P.
AU - Martinez, Daniel
AU - Pogoriler, Jennifer
AU - Krytska, Kateryna
AU - Patel, Khushbu
AU - Groff, David
AU - Tsang, Matthew
AU - Ghilu, Samson
AU - Wang, Yifei
AU - Seaman, Steven
AU - Feng, Yang
AU - St Croix, Brad
AU - Gorlick, Richard
AU - Kurmasheva, Raushan
AU - Houghton, Peter J.
AU - Maris, John M.
N1 - Funding Information:
This work was supported by NCI U01 CA199287 (to J.M. Maris), NCI R35 CA220500 (to J.M. Maris), NCI U01 CA199221 (to Richard G. Gorlick), NCI U01 CA199297(toP.J.Houghton),CPRITRP160716(toP.J. Houghton), NCIF31CA239424 (to N.M. Kendsersky), NCI F31 CA254244 (to J. Lindsay), NCI U01 CA199222 (to Gregory J. Gatto), and the Giulio D’Angio Endowed Chair (to J.M. Maris).
Publisher Copyright:
© American Association for Cancer Research.
PY - 2021/5
Y1 - 2021/5
N2 - 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 (PDX) and cell line–derived xenograft (CDX) models. Experimental Design: 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 (N ¼ 3), rhabdomyosarcoma (N ¼ 4), Wilms tumors (N ¼ 2), osteosarcoma (N ¼ 5), and neuroblastoma (N ¼ 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. 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 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. Conclusions: m276-SL-PBD has significant antitumor activity across a broad panel of pediatric solid tumor PDX models.
AB - 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 (PDX) and cell line–derived xenograft (CDX) models. Experimental Design: 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 (N ¼ 3), rhabdomyosarcoma (N ¼ 4), Wilms tumors (N ¼ 2), osteosarcoma (N ¼ 5), and neuroblastoma (N ¼ 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. 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 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. Conclusions: m276-SL-PBD has significant antitumor activity across a broad panel of pediatric solid tumor PDX models.
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U2 - 10.1158/1078-0432.CCR-20-4221
DO - 10.1158/1078-0432.CCR-20-4221
M3 - Article
C2 - 33619171
AN - SCOPUS:85103876224
SN - 1078-0432
VL - 27
SP - 2938
EP - 2946
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -