Abstract 5680: Tetra-specific antibody GNC-039: guidance and navigation control (GNC) molecule development for treatment of EGFRvIII+ malignancies
Authors: Khalili Jahan Salar , Xiao Sa , Zhu Yi 
Published: June 2023

Abstract
One of the primary challenges in the targeting of the tumor specific antigen EGFRvIII is the expression of the antigen among tumor cells in cranial glioblastoma tumors. The development of GNC-039 is based on the capability of this protein to redirect T cell cytolysis toward the tumor specific antigen EGFRvIII and guide T cells in the tumor microenvironment. Here we demonstrate that the tetraspecific Guidance and Navigation Control (GNC) antibody, GNC-039, binds to EGFRvIII, CD3, PD-L1, and 4-1BB and mediates T cell cytolysis of the human glioblastoma cancer cell line U87 expressing EGFRvIII in the in vitro tumor spheroid model.
When delivered intravenously, the biodistribution of GNC-039 is an important factor in the development of this intracranial tumor targeting biologic. To better understand the biodistribution of GNC-039, Orthotopic Patient Derived Xenograft (PDX) models of Glioma were utilized and vivo-tag680XL-labelled GNC-039 was evaluable by total flux in the Brain area. Multiple IV infusions of GNC-039 were carried out over the study period (29 Days). Groups received either GNC-039 (n=5), GNC-039 with engrafted PBMC (n=5), Temozolomide(n=5), or Vehicle (n=5). The PDX model was sensitive to Temozolomide, 0/5 mice residual tumor, medial overall survival (mOS) of 15 days. In the Vehicle treatment group, 5/5 mice had residual tumor, mOS was 26 days. Mice receiving GNC-039 without PBMC, could partially respond to the treatment, in this group 3/5 animal had residual brain tumors by end of study, but with only a mOS of 15 days. In these animals, the GNC-039 accumulated in the brain region to its maximal level by the third dose on Day 7 and stayed consistently at that level for the duration of the study period. However, in the mouse group with engraft PBMC, the level of GNC-039 in the brain region could exceed that of the drug when infused alone. Mice receiving GNC-039 with engrafted PBMC completely responded to treatment, 5/5 mice in the group had no residual brain tumor, and a mOS of 20 days. In the presence of the engrafted PBMC, the increased level of GNC-039 in the brain region was delayed compared with treatment in the absence of PBMC. As a point of comparison, the Day 7 levels from GNC-039 treatment alone were not reached until Day 15 in presence of PBMC. However, beyond this timepoint, the level of GNC-039 in the brain region was significantly increased due to the engrafted PBMC.
Collectively this data indicates the functionality of GNC-039 as a multi-specific T cell engager with the potential to target EGFRvIII+ cancer cell cytolysis in primary brain disease. The clinical phase I-b study of GNC-039 is under way and the available data exhibit strong signals of efficacy with acceptable tolerability.
Citation Format: Jahan Salar Khalili, Sa Xiao, Yi Zhu. Tetra-specific antibody GNC-039: guidance and navigation control (GNC) molecule development for treatment of EGFRvIII+ malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5680.