Initial testing of m276-PBD CD276 antibody-drug conjugate in preclinical models of pediatric cancers by the Pediatric Preclinical Testing Consortium (PPTC)

Abstract

Meeting Abstract C003
Purpose: CD276 (B7-H3) is an immunoregulatory molecule that is reported to be widely expressed in pediatric embryonal tumors, pediatric sarcomas, and tumor infiltrating blood vessels. CD276 protein is expressed at low levels on several normal tissues, including cerebral cortex, liver and germinal lymph node. m276 is a fully-human IgG1 that binds with similar affinity to both mouse CD276 (24 nM kD) and human CD276 (29 nM kD) (Seaman et al., Cancer Cell, 2017). To generate an antibody-drug conjugate, m276 was site-specifically conjugated to the DNA damaging agent pyrrolobenzodiazepine (PBD) via a cleavable valine-alanine linker, providing m276-PBD with a Drug-to-Antibody Ratio (DAR) of 2. Here we examined the antitumor activity of m276-PBD against preclinical xenograft models of pediatric solid tumors. Experimental Procedures: Expression of CD276 across PPTC xenograft models (>200) representing leukemias, brain tumors and solid tumors was determined by RNA seq, and additionally in neuroblastoma models by IHC. Xenograft experiments were undertaken in heterotopic models using standard methods of the PPTC. Response criteria were tumor regression (PR, CR, maintained CR [at 6 weeks]) and Event-Free Survival (EFS). m276-PBD was administered by intraperitoneal injection at a dose of 0.5 mg/kg, once weekly x 3 consecutive weeks. Results: CD276 expression was high in most solid tumors (median 41 FPKM) with highest expression in osteosarcoma. Neuroblastoma, rhabdomyosarcoma, Wilms tumor and embryonal brain tumor models had similar levels of expression, whereas ALL models showed low expression. In vivo efficacy studies are ongoing, but data to date are available for 5 osteosarcoma, 4 rhabdomyosarcoma, 2 Ewing sarcoma and 2 Wilms tumors. Maintained Complete Response (MCR) at 6 weeks was attained in 2/5 osteosarcoma, 3/4 rhabdomyosarcoma and 1/2 Ewing sarcoma. CR was achieved in 1/2 Wilms tumor, 1/2 rhabdomyosarcoma, and 2/5 osteosarcoma models. Body weight loss (<3%) was noted in only one study. Conclusions: Expression of CD276 was high in most PPTC solid tumor models. mCD276-PBD was highly active against most models tested inducing long-lasting CR’s. There was no toxicity, suggesting that this agent has an effective therapeutic window in these models. Mature results (100 days observation) and additional results for neuroblastoma models will be presented.