Testing of B7-H3 targeting antibody-drug conjugate (ADC) MGC018 in models of pediatric solid tumors by the Pediatric Preclinical Testing Consortium (PPTC).
Authors: Kurmasheva Raushan , Mosse Yael P. , Del Pozo Vanessa , Earley Eric J , Erickson Stephen W , Groff David , Kolb E. Anders , Krytska Kateryna , Smith Malcolm A. , Tsang Matthew , Teicher Beverly A. , Gorlick Richard Greg , Maris John M. , Houghton Peter 
Published: June 2021

10037

Background: B7-H3 (encoded by the CD276 gene) is an immunoregulatory molecule that is widely expressed in pediatric embryonal tumors and sarcomas, while expression is limited for normal tissues. Among PPTC models, osteosarcoma models showed highest CD276 transcript levels followed by Wilms tumor, neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma. Protein expression by IHC generally followed expression at the RNA level, with high expression by IHC observed across a range of models. MGC018 is a duocarmycin-based humanized ADC targeting B7-H3 that shows selective cytotoxicity for B7-H3 expressing cancer cells, robust in vivo activity against a range of adult cancer preclinical models, a favorable pharmacokinetic and safety profile in cynomolgus monkeys, and has entered clinical testing for adults with cancer. Herein we report the in vivo antitumor activity of MGC018 against preclinical models of pediatric solid tumors. Methods: MGC018 was tested at 6 mg/kg administered intraperitoneally (IP) on Day 1. SYD988, an anti-CD20 ADC with the same linker and payload as MGC018, was used as a control arm at 6 mg/kg IP on Day 1. Osteosarcoma models, due to their slower growth kinetics and lower rates of tumor regression, were tested with n = 10 mice per arm, while the sarcoma and neuroblastoma models were tested with n of 1 or n of 2 designs, respectively. Activity was evaluated using response criteria mirroring clinical criteria (progressive disease (PD), stable disease (SD), partial response (PR), complete response (CR), and maintained CR (MCR)], by minimum relative tumor volume across all models, and by event-free survival (EFS) comparisons between treatment groups. Results: For neuroblastoma models (n = 9), 3 and 2 neuroblastoma models showed objective responses (PR/CR/MCR) or SD, respectively, to MGC018, while none showed an objective response or SD to SYD988. For osteosarcoma, results are mature for 1 of 5 models, with this model showing an MCR response to MGC018 and a PD response to SYD988. For Ewing sarcoma (n = 5), a PR and MCR were observed to MGC018 with the remaining models showing PD; for SYD988 a single CR was observed with the remaining 4 models showing PD. For rhabdomyosarcoma (n = 3) 2 MCR and 1 PD were noted for MGC018, while only PD was noted for SYD988. EFS duration exceeding 100 days to a single dose of MGC018 was observed for 2 rhabdomyosarcoma, 1 Ewing sarcoma, and 1 neuroblastoma model. Evaluation of the relationship between B7-H3 expression and response to MGC018 will be performed when results from all studies are completed. Conclusions: B7-H3 is an important target for immuno-oncology agents for childhood cancers. Our results provide proof-of-principle for the ability of MGC018 to produce profound antitumor activity in select pediatric solid tumor models in a B7-H3 specific manner.