Abstract
B cell malignancies treated with CD19-directed immunotherapies can relapse, in some cases due to clonal selection for reduced CD19 antigen expression or enhancement of immunosuppressive phenotypes. Here we demonstrate that a Guidance and Navigation Control (GNC) tetra-specific antibody, GNC-038, binds to CD19, CD3, PD-L1, and 4-1BB and mediates cytolysis of human leukemia and lymphoma cells by T cells.
Redirected T cell cytolysis (RTCC) occurs in the presence of GNC-038 (Emfizatamab), resulting in the killing of CD19+ leukemia and lymphoma cell lines. The cytolytic functions induced by GNC-038 are similar to Blinatumomab in vitro, as indicated by T cell degranulation and production of IFN-gamma. Human T cells in PBMC exposed to GNC-038 in vitro proliferate in a dose-dependent fashion. Proliferation is further enhanced upon rechallenge with leukemic target cells. Proliferation of T cells from individuals with higher % PD-1+ and Effector polarized compartments is enhanced by GNC-038 compared to Blinatumomab. To evaluate the contribution of each binding domain of GNC-038 in mediating RTCC function, versions of GNC-038 were prepared, replacing each antigen binding domain with anti-FITC binding domains. Under assay conditions using PBMC for RTCC toward the CD19+ target cell line Nalm-6, the results demonstrate the contribution of each domain to the overall, anti-leukemic cytolytic activity.
To evaluate the potential for GNC-038 to mediate cytokine release syndrome, the molecule is evaluated in soluble, and plate bound formats in the presence of PBMC and CD19+ leukemic targets cells. In comparison to Blinatumomab, the production of cytokines is comparable, with some notable differences. PBMC exposed to soluble GNC-038 for 48 hours produced more IFN-γ, IL-2 and TNF-α, while showing no significant difference in production of IL-6. Based on these results, the primary indicator of CRS, IL-6, does not suggest increased risk compared to Blinatumomab, while the type of T cell activity induced by GNC-038 in PBMC with leukemia cells is distinct.
Collectively, the GNC-038 represents a class of multi-specific and multi-modal immune cell engagers with potential to mediate CD19+ cancer killing, while also increasing the T cell compartment’s therapeutic potential to respond to T cell redirection upon subsequent cycles of therapy. The clinical phase I-b study of GNC-038 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-038: guidance and navigation gontrol (GNC) molecule development for treatment of CD19+ 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 5681.
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