Anti-DR5 (Drozitumab) h(41BB-CD3ζ) CAR, pCDCAR1 vector

All products and services are For Research Use Only and CANNOT be used in the treatment or diagnosis of disease.

Details

Target
DR5

Targeting Cell Type
T cell

Targeting Diseases
colorectal cancer, hepatocellular carcinoma, glioma, renal cancer, breast cancer

Generation
Second

Vector Name
pCDCAR1

Vector Length
~8kb

Vector Type
Lentiviral vector

Receptor Construction
scFv-CD28-CD3ζ

Discription of Signaling Cassetes
CD28
CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide costimulatory signals required for T cell activation and survival. CD28 is the receptor for CD80 (B7.1) and CD86 (B7.2) proteins which are expressed on antigen-presenting cells (APC). CD28 modulates the primary TCR/CD3ζ signal in a different fashion than the late costimulatory elements OX40 and 4-1BB. CD28 enhances the expression of downstream regulators that impact on T-cell proliferation, death, differentiation, and effector functions. CAR+ T cells containing the CD28 endodomain showed strikingly enhanced sustained T cell activation, growth, survival. And CD28 results in a brightly expressed, stable receptor as the transmembrane domain. Including CD28 costimulatory domains in CARs led to enhanced anti-malignancy efficacy.
CD3ζ
CD3ζ, also known as T-cell receptor zeta, which together with T-cell receptor and CD3γ, δ , ε chain, forms the TCR-CD3 complex. ζ was expressed independently from the complex. The zeta chain plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. CD3-zeta, which contains 3 ITAMs, is the most commonly used endodomain component of CARs. It transmits an activation signal to the T cell after antigen is bound. CD3-zeta may not provide a fully competent activation signal and additional co-stimulatory signaling is needed. For example, chimeric CD28 and OX40 can be used with CD3-zeta to transmit a proliferative/survival signal, or all three can be used together.

Target

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Published Data

CAR scFv data Inhibit

Fig.2 The growth of three different established patient-derived xenografts is inhibited by treatment with drozitumab.

CAR Construction :

Fig.2 The growth of three different established patient-derived xenografts is inhibited by treatment with drozitumab.

SCID mice implanted with tumors.

Eng, J. W. L., Mace, T. A., Sharma, R., Twum, D. Y., Peng, P., Gibbs, J. F., ... & Hylander, B. L. (2016). Pancreatic cancer stem cells in patient pancreatic xenografts are sensitive to drozitumab, an agonistic antibody against DR5. Journal for immunotherapy of cancer, 4, 1-11.

CAR scFv data FCM

Fig.3 Cancer stems cells undergo apoptosis following treatment with drozitumab.

CAR Construction :

Fig.3 Cancer stems cells undergo apoptosis following treatment with drozitumab.

Dissociated tumor cells from 11424, 14244 and 12424 treated in vitro with 10 μg/ml of drozitumab antibody for 1 h and incubated for 7 h with 10 μg/ml of anti-human Fc IgG antibody.

CAR scFv data FCM

Fig.4 Mice were treated with 200 μg drozitumab and tumors were resected, disaggregated and percentage of cleaved caspase-3 in CSCs vs. bulk tumor cells analyzed by flow cytometry.

CAR Construction :

Fig.4 Mice were treated with 200 μg drozitumab and tumors were resected, disaggregated and percentage of cleaved caspase-3 in CSCs vs. bulk tumor cells analyzed by flow cytometry.

Treatment of tumor bearing mice in vivo with drozitumab induces apoptosis primarily in triple positive cells.

CAR scFv data FuncS

Fig.5 Drozitumab treatment depletes DR5+ cells in vitro.

CAR Construction :

Fig.5 Drozitumab treatment depletes DR5+ cells in vitro.

Experiment performed twice in triplicate.

CAR scFv data ELISA

Fig.6 Drozitumab (DRO) with anti-Fc antibody treatment induces apoptosis in the sensitive RMS cells.

CAR Construction :

Fig.6 Drozitumab (DRO) with anti-Fc antibody treatment induces apoptosis in the sensitive RMS cells.

The sensitive Rh18 cells were treated with drozitumab or a 1:1 ratio of drozitumab anti-Fc antibodies at the indicated doses for 72 hours prior to the viability assay (top).

Kang, Z., Chen, J. J., Yu, Y., Li, B., Sun, S. Y., Zhang, B., & Cao, L. (2011). Drozitumab, a Human Antibody to Death Receptor 5, Has Potent Antitumor Activity against Rhabdomyosarcoma with the Expression of Caspase-8 Predictive of ResponsePreclinical Evaluation of DR5 Antibody Drozitumab in RMS. Clinical Cancer Research, 17(10), 3181-3192.

CAR scFv data FCM

Fig.7 The cell surface expression of DR4 and DR5 was analyzed by FACS in selected TRAIL and DR5 resistant (R) or sensitive (S) cells.

CAR Construction :

Fig.7 The cell surface expression of DR4 and DR5 was analyzed by FACS in selected TRAIL and DR5 resistant (R) or sensitive (S) cells.

TRAIL reduces RMS cell viability mediated via the DR5 receptor.

CAR scFv data FCM

Fig.1 Flow Cytometry analysis of cell surface expression of Apo2L/TRAIL death receptors in drozitumab-sensitive MDA-MB-231-TXSA cells versus resistant MDA-MB-231-droz-R cells.

CAR Construction :

Fig.1 Flow Cytometry analysis of cell surface expression of Apo2L/TRAIL death receptors in drozitumab-sensitive MDA-MB-231-TXSA cells versus resistant MDA-MB-231-droz-R cells.

Graphs were obtained after staining with anti human DR5 monoclonal antibodies.

Zinonos, I., Labrinidis, A., Liapis, V., Hay, S., Panagopoulos, V., Denichilo, M., ... & Evdokiou, A. (2014). Doxorubicin overcomes resistance to drozitumab by antagonizing inhibitor of apoptosis proteins (IAPs). Anticancer Research, 34(12), 7007-7020.

More Published Data More Published Data

For research use only. Not intended for any clinical use. No products from Creative Biolabs may be resold, modified for resale or used to manufacture commercial products without prior written approval from Creative Biolabs.

Anti-DR5 (Drozitumab) h(41BB-CD3ζ) CAR, pCDCAR1 (CAR-ZP1233)

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