Preclinical Assessment of AMG 596, a Bispecific T-cell Engager (BiTE) Immunotherapy Targeting the Tumor-specific Antigen EGFRvIII
- 25 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 20 (5), 925-933
- https://doi.org/10.1158/1535-7163.mct-20-0508
Abstract
AMG 596 is a BiTE® (bispecific T cell engager) immuno-oncology therapy in clinical development for treatment of glioblastoma multiforme (GBM), the most common primary brain tumor in adults with limited therapeutic options. AMG 596 is composed of two single chain variable fragments that simultaneously bind to the tumor-specific antigen epidermal growth factor receptor variant III (EGFRvIII) on GBM cells and to CD3 on T cells, thereby activating T cells to proliferate and secrete cytotoxic substances that induce lysis of the bound tumor cell. T cell-redirected lysis by AMG 596 is very potent; in vitro studies revealed effective concentration for 50% response (EC50) values in the low picomolar range, and in vivo studies showed that AMG 596 treatment significantly increased the overall survival of mice bearing EGFRvIII-expressing orthotopic tumors. In addition, AMG 596 activity is highly specific; no AMG 596-induced T cell activity can be observed in assays with EGFRvIII-negative GBM cells, and no signs of toxicity and activity were observed in cynomolgus monkeys, which lack expression of EGFRvIII on normal tissues. With EGFRvIII-expressing GBM cells, we show shedding of EGFRvIII-containing membrane vesicles followed by vesicle uptake and EGFRvIII cell surface presentation by EGFRvIII noncoding GBM cells. Cell membrane presentation of EGFRvIII following microvesicle (MV) transfer allows engagement by AMG 596, resulting in T cell activation and T cell-dependent lysis of GBM cells. Together, these data show a compelling preclinical efficacy and safety profile of AMG 596, supporting its development as a novel immune therapy for treatment of GBM.Keywords
Funding Information
- Amgen
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