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A heterogeneous and infiltrating tumor like glioblastoma (GBM) cannot be effectively treated with a single-targeted therapy. Hence, targeting several GBM-associated factors that are responsible for the disease progression and/or recurrence at once is a way to address the issue of tumor heterogeneity. Building on a Phase I clinical trial of a cytotoxic cocktail targeting IL-13-RA2 and EphA2 receptors showing dramatic anti-tumor responses in dogs with spontaneous gliomas, we have developed multivalent single pharmaceutical agents that target four specific to GBM receptors: IL-13RA2, EphA2, EphA3, and EphB2. The combined expression of these receptors spans almost 100% of the tumor microenvironment of pathobiological importance, such as tumor initiating cells, infiltrating cells, neo-vasculature, and GBM-infiltrating cells of monocytic origin like macrophages. Variants of this multivalent protein termed QUAD 2.0 and 3.0 contain an IgG1 scaffold, ephrinA5, which is a ligand for the EphA2, EphA3, and EphB2 receptors, and IL-13.E13K, a mutated version of interleukin 13 (IL-13) binding preferentially to IL-13RA2. In QUAD 3.0, a cysteine was added to the C-terminal end of QUAD 2.0 to allow effective conjugation to cytotoxic agents/labels. All QUAD variants bound effectively to the four receptors using ELISA with KD values of 100–200 pM for EphA2, EphA3, and IL-13RA2, and 700 pM-4 nM for EphB2, and downregulated the EphA2 and EphA3 receptors in GBM cells. QUAD 2.0 and 3.0 were conjugated to a modified form of Pseudomonas Exotoxin A and a modified doxorubicin. The conjugates were highly cytotoxic to established and primary GBM cells with IC50s &lt; 1.0 nM. Intracranial injections (1.3 mM, 5µL) of the conjugates were well tolerated in mice. Thus, targeting multiple receptors with a single multivalent protein is possible. One additional advantage in using these targeted cytotoxins is that they produce immunogenic cell death and can be combined with other approaches activating the immune system.

EXTH-54. MULTIVALENT TARGETED PROTEINS FOR GLIOBLASTOMA TREATMENT