Description

Preclinical evaluation of a BiTE^® antibody construct targeting EGFRvIII to treat Glioblastoma multiforme

Alexander Sternjak, Joachim Wahl, Ines Hermann, Oliver Thomas, Markus Muenz, Benno Rattel, Peter Kufer and Matthias Friedrich

Amgen Research (Munich) GmbH

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, and has an aggressive phenotype resulting in rapid progression and very poor prognosis. There is an urgent need for new therapeutic options. Accordingly, we have developed a bispecific T cell engaging (BiTE^®) antibody construct, designated EGFRvIII BiTE^®, for the treatment of GBM.

The EGFRvIII BiTE^® is composed of two tandemly arranged single-chain antibody fragments specific for human and cynomolgus monkey CD3 and the human epidermal growth factor receptor variant III (EGFRvIII). EGFRvIII is a deletion mutant of EGFR and is described as a highly tumor specific antigen expressed in up to 30% of GBM cases. By simultaneously binding to CD3-positive T cells and EGFRvIII-expressing tumor cells, the EGFRvIII BiTE^® very efficiently and specifically redirects T cells to lyse EGFRvIII-positive tumor cell lines as observed in flow-cytometric based cytotoxicity assays. Intravenous administration of the EGFRvIII BiTE^® for 16 consecutive days to NOD/Scid mice orthotopically xenografted with glioblastoma cells and intraperitoneally reconstituted with human T cells resulted in a significantly prolonged survival compared to vehicle-treated mice. Furthermore, the EGFRvIII BiTE^® was well tolerated by cynomolgus monkeys when administered by continuous intravenous infusion for seven days.

Our data demonstrate that the EGFRvIII BiTE^® very potently mediated the lysis of EGFRvIII-positive tumor cell lines (EC₅₀ values below 1 pM), significantly prolonged the survival of tumor bearing mice in an orthotopic tumor model (p < 0.001), and caused no toxicity in a dose range finding study in cynomolgus monkey. Combining these data with the very specific expression of EGFRvIII on tumor cells, we see a high potential for the EGFRvIII BiTE^® to successfully treat EGFRvIII-positive GBM.