Phase 1/1b Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 596 as Monotherapy and in Combination With AMG 404 in Subjects With Glioblastoma or Malignant Glioma Expressing Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII)
This is a Phase 1/1b Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 596 monotherapy or in combination with AMG 404 in Subjects with Glioblastoma or Malignant Glioma Expressing Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII). This is a first in human (FIH), open-label, sequential-dose-escalation study in subjects with EGFRvIII-positive glioblastoma or malignant glioma. This study will enroll 2 groups of subjects according to disease stage, recurrent disease (Group 1) and maintenance treatment after SoC in newly diagnosed disease (Group 2).
Preclinical Assessment of AMG 596, a BiTE® (Bispecific T-Cell Engager) Immune Therapy Targeting the Tumor-Specific Antigen EGFRvIII.
2区 · 医学
作者: Alexander Sternjak ; Fei Lee ; Oliver Thomas ; Mercedesz Balazs ; Joachim Wahl ; Grit Lorenczewski ; Ines Ullrich ; Markus Muenz ; Benno Rattel ; Julie M Ballis ; Matthias Friedrich
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.
2020-04-14·Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi
[CD19 antigen loss after treatment of Bispecific T-cell Engager and effective response to salvage bispecific CAR-T therapy in B cell acute lymphoblastic leukemia: a case report and literature review].
作者: X H Fu ; Y Wang ; H J Wang ; S N Wei ; Y X Xu ; H Y Xing ; K J Tang ; Z Tian ; Q Rao ; J X Wang ; M Wang
Objective: To analyze the influence of CD19 isoforms to the efficacy of CD19/CD3 Bispecific T-cell Engager (BiTE) antibody, and explore the resistance mechanism of BiTE immunotherapy. Methods: Semi-quantitative RT-PCR (qRT-PCR) was used to detect the expression of CD19 mRNA isoforms before and after BiTE treatment in a patient with CD19(+) B cell acute lymphoblastic leukemia (ALL) . CD19 isoforms were analyzed by Sanger sequencing. Flow cytometry and transcriptome sequencing were performed to analyze the expression of cell lineage specific molecules before and after BiTE treatment. Results: The expression of CD19 isoform with exon 2 deletion was identified at diagnosis. After relapsed and treatment of BiTE antibody, the patient did not achieve remission and CD19 antigen on leukemic cells turned negative detected by flow cytometry after BiTE treatment. However the expression ratio of CD19 isoform with exon 2 deletion was not increased. Flow cytometry phenotype and transcriptome sequencing confirmed that no linage switching developed, which suggested the expression of CD19 isoform caused by exon alternative splicing and lineage switching was not related to CD19 epitope loss in this patient. This patient achieved complete remission by sequential administration of self-developed CD22 CAR-T and CD19 CAR-T after disease progression. Conclusion: Targeting or combining an alternative antigen specific CAR-T may be a promising treatment option after losing CD19 expression in relapsed ALL.
2015-04-01·Journal of Biomolecular Screening
Characterization of bispecific T-cell engager (BiTE) antibodies with a high-capacity T-cell dependent cellular cytotoxicity (TDCC) assay
作者: Nazarian, Aaron A. ; Archibeque, Ivonne L. ; Nguyen, Yen H. ; Wang, Paul ; Sinclair, Angus M. ; Powers, David A.
The Bispecific T-cell Engager (BiTE) antibody modality is a clinically validated immunotherapeutic approach for targeting tumors. Using T-cell dependent cellular cytotoxicity (TDCC) assays, we measure the percentage of specific cytotoxicity induced when a BiTE molecule engages T-cells, redirects T-cell mediated cytolysis, and ultimately kills target cells. We establish a novel luminescence-based TDCC assay quantified by measuring cell viability via constitutive expression of luciferase. The luciferase-based TDCC assay performance is valid and comparable to an adenosine triphosphate (ATP)-based detection method. We demonstrate that the luciferase-based TDCC assay is an efficient homogeneous assay format that is amenable to both suspension and adherent target cells. The luciferase-based TDCC assay eliminates the need for plate-washing protocols, allowing for higher-throughput screening of BiTE antibodies and better data quality. Assay capacity is also improved by performing serial dilutions of BiTE antibodies in 384-well format with an automated liquid handler. We describe here a robust, homogeneous TDCC assay platform with capacity for in vitro assessment of BiTE antibody potency and efficacy using multiple tumor cell lines and T-cell donors.