Abstract P134: Novel EGFRvIII-selective antibody-drug conjugate REGN3124-PBD is strongly efficacious against orthotopic glioblastoma multiforme patient derived xenografts
Authors: Kelly Marcus P. , Makonnen Sosina , Hickey Carlos , Mao Shu , Zhao Feng , Kunz Arthur , Delfino Frank , Nittoli Thomas , Ma Dangshe , Olson William C. , Thurston Gavin , Kirshner Jessica R. 
Published: December 2021

Glioblastoma Multiforme (GBM) is a highly aggressive cancer with few specific molecular targets and poor therapeutic outcome. Epidermal Growth Factor Receptor variant III (EGFRvIII) is a promising target for the treatment of GBM due to its exclusive expression in GBM. However, prior therapeutics have failed in part due to the development of EGFRvIII negative tumors cells from heterogenous tumor populations. We therefore developed a potent antibody-drug conjugate with bystander killing capabilities to target heterogeneous EGFRvIII-expressing GBM tumors. REGN3124 is a fully human EGFRvIII-selective antibody that also demonstrates some binding to amplified wild-type EGFR. REGN3124 was conjugated to the pyrrolobenzodiazepine (PBD) linker-payload SG-3249 to form REGN3124-PBD, and the cytotoxicity and cellular bystander killing activity was characterized in vitro. Initial in vivo activity of REGN3124-PBD was assessed in subcutaneous (s.c.) U251/EGFRvIII and U87/EGFRvIII cell line xenografts and then in s.c. EGFRvIII-positive patient derived xenograft (PDX) models (GBM6 and GBM59). Immunohistochemistry demonstrated heterogenous expression of EGFRvIII in GBM59 tumors. Lastly, efficacy was assessed in animals with established intracranial GBM6 or GBM59 tumors to examine the activity of REGN3124-PBD in an orthotopic setting. REGN3124-PBD demonstrated sub-nM cytotoxicity in vitro and clear bystander killing of EGFRvIII negative U251 cells following targeting of U251/EGFRvIII cells. A single dose of 0.38 mg/kg REGN3124-PBD (3.4 drug: antibody ratio) induced sustained regression of both s.c. U251/EGFRvIII and U87/EGFRvIII xenografts. A single dose of 0.53 mg/kg REGN3124-PBD induced complete regression of s.c. GBM6 PDX tumors and sustained regression of GBM59 tumors. Single dose of 0.53 mg/kg REGN3124-PBD significantly prolonged survival of mice with established intracranial GBM6 or GBM59 tumors, with 5/8 and 7/8 animals surviving &gt;90 days post-treatment, respectively. The high unmet need for effective therapies combined with the potent anti-tumor activity observed, including in those with heterogenous expression of EGFRvIII, support continued assessment of REGN3124-PBD as a novel therapy for treatment of GBM.

Citation Format: Marcus P. Kelly, Sosina Makonnen, Carlos Hickey, Shu Mao, Feng Zhao, Arthur Kunz, Frank Delfino, Thomas Nittoli, Dangshe Ma, William C. Olson, Gavin Thurston, Jessica R. Kirshner. Novel EGFRvIII-selective antibody-drug conjugate REGN3124-PBD is strongly efficacious against orthotopic glioblastoma multiforme patient derived xenografts [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P134.