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Preclinical Assessment of AMG 596, a Bispecific T-cell Engager (BiTE) Immunotherapy Targeting the Tumor-specific Antigen EGFRvIII
- Source :
- Molecular cancer therapeutics. 20(5)
- Publication Year :
- 2020
-
Abstract
- AMG 596 is a bispecific T-cell engager (BiTE) 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, EGFR 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 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 showed 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 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 immunotherapy for treatment of GBM.
- Subjects :
- 0301 basic medicine
Cancer Research
medicine.medical_treatment
CD3
T cell
Cell
03 medical and health sciences
Mice
0302 clinical medicine
Antigen
In vivo
Cell Line, Tumor
Antibodies, Bispecific
medicine
Animals
Humans
biology
Chemistry
Brain Neoplasms
Microvesicle
Immunotherapy
In vitro
ErbB Receptors
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Cancer research
biology.protein
Glioblastoma
Subjects
Details
- ISSN :
- 15388514
- Volume :
- 20
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Molecular cancer therapeutics
- Accession number :
- edsair.doi.dedup.....ef60feab2eb1f94492e7710cbc8b7c94