Efficacy of ABBV-706, a SEZ6-targeted topoisomerase 1 inhibitor ADC: A report from the Pediatric Preclinical In Vivo Testing (PIVOT) Program

Introduction: ABBV-706 is an antibody-drug conjugate (ADC) composed of a monoclonal antibody targeting the seizure-related homolog 6 (SEZ6) surface protein linked to topoisomerase 1 inhibitor payload. A Phase 1 trial of ABBV-706 is underway in adults with SEZ6 expressing relapsed solid tumors (NCT05599984). ABBV-706 became of interest as SEZ6 is highly expressed in many pediatric cancers. The goal was to evaluate ABBV-706 in models of childhood cancers with notable SEZ6 expression: neuroblastoma (NB), medulloblastoma (MB), retinoblastoma (RB), and alveolar rhabdomyosarcoma (ARMS) and compare the activity to vehicle and isotype non-target control ADC (IC-ADC). Methods: Pediatric xenograft models were screened for SEZ6 expression. Single agent in vivo studies were completed in NB, MB, RB, and ARMS models with varying SEZ6 expression. After engraftment, 2 total doses of ABBV-706 or IC-ADC were given by IP injection 3 weeks apart at 2 dose levels (DL1, DL2). Efficacy was assessed by median event free survival (KM med, in days) and objective response measure (ORM, Ped Blood Cancer 2007;49:928-940). ORM defines an objective response as partial, complete, or maintained complete response (PR, CR, and MCR) compared to stable disease (SD) or progressive disease, with or without growth delay (PD2 and PD1, respectively). Results: ABBV-706 showed efficacy in a broad range of SEZ6 expressing non-CNS (NB, RB, ARMS) models. At DL1, PR, CR, or MCR responses were seen in 8 of 11 models. At DL2, 9 of 11 models had PR, CR, or MCR responses. For most models, ABBV-706 was more active than IC-ADC. Survival advantage was observed in 1 of 2 MB models. Conclusion: We showed high anti-tumor activity for ABBV-706 in multiple SEZ6 expressing models and enhanced efficacy versus IC-ADC. Due to high expression of SEZ6 in several pediatric histologies, ABBV-706 has potential for clinical activity in patients with these cancers. Model SEZ6 mRNA (FPKM) Cancer Type Vehicle KM med Vehicle ORM ABBV-706 DL1 KM med ABBV-706 DL1 ORM ABBV-706 DL2 KM med ABBV-706 DL2 ORM IC-ADC DL1 KM med IC-ADC DL1 ORM IC-ADC DL2 KM med IC-ADC DL2 ORM COG-N-424x 46.1 NB 8.6 PD 82.8* MCR >99* MCR 6 PD1 13.6 PD1 COG-N-496x 59.9 NB 11.1 PD >103* MCR >103 MCR 8.3 PD1 >103 MCR COG-N-561x 13 NB 8.2 PD 78.4* PR 101* MCR 13.7 PD1 37 PD2 NB-1691 17.9 NB 7.9 PD 19.4* PD2 34.3* PD2 10.7 PD1 10.8 PD1 SK-N-AS 0.06 NB 9.7 PD 9.4 PD1 10.5 PD1 8.74 PD1 12.3 PD1 SJRB012408_X2 53.8 RB 35 PD 126* MCR 108.5 PR 42 PD1 70 PD1 SJRB063836_X1 78.6 RB 35 PD 140* MCR 140* MCR 35 PD1 87.5 SD SJRHB030765_X1 119.8 ARMS 35 PD 63* PD1 140* PR 42 PD1 70 PD1 SJRHB030787_X1 129.3 ARMS 35 PD 105* CR 91 CR 63 PD1 84 SD SJRHB031320_X1 21.8 ARMS 35 PD 98* PR 108.5* PR 66.5 PD1 91 SD SJRHB046156_X1 111.7 ARMS 14 PD 84 PR 105* CR 21 PD1 21 PD1 Icb-2164MB 166.4 MB 69.5 - 76 - 91* - 77.5 - 72 - Icb-3130MB 46.1 MB 90 - 137 - 148.5 - 121.5 - 117.5 - *indicates p-value <0.05 compared to matched IC-ADC