Bi-specific T-cell engager
Bi-specific T-cell engagers (BiTEs) are a class of artificial bispecific monoclonal antibodies that are investigated for the use as anti-cancer drugs. They direct a host's immune system, more specifically the T cells' cytotoxic activity, against cancer cells. BiTE is a registered trademark of Micromet AG.
BiTEs are fusion proteins consisting of two single-chain variable fragments (scFvs) of different antibodies, or amino acid sequences from four different genes, on a single peptide chain of about 55 kilodaltons. One of the scFvs binds to T cells via the CD3 receptor, and the other to a tumor cell via a tumor specific molecule.
Mechanism of action
Like other bispecific antibodies, and unlike ordinary monoclonal antibodies, BiTEs form a link between T cells and tumor cells. This causes T cells to exert cytotoxic activity on tumor cells by producing proteins like perforin and granzymes, independently of the presence of MHC I or co-stimulatory molecules. These proteins enter tumor cells and initiate the cell's apoptosis.
This action mimics physiological processes observed during T cell attacks against tumor cells.
- Blinatumomab (MT103): for the treatment of non-Hodgkin’s lymphoma and acute lymphoblastic leukemia; directed towards CD19, a surface molecule expressed on B cells
- MT110: for the treatment of gastrointestinal and lung cancers; directed towards the EpCAM antigen
Utilizing the same technology, melanoma (with MCSP specific BiTEs) and acute myeloid leukemia (with CD33 specific BiTEs) can be targeted. Research in this area is currently ongoing. Another avenue for novel anti-cancer therapies is re-engineering some of the currently used conventional antibodies like trastuzumab (targeting HER2/neu), cetuximab and panitumumab (both targeting the EGF receptor), using the BiTE approach. BiTEs against CD66e and EphA2 are being developed as well.
- "US Trademark registration no. 3,068,856, serial number 78/040,636.". US Patent and Trademark Office.
- Helwick, Caroline (1 June 2008). "Novel BiTE antibody mediates contact between T cells and cancer cells". Oncology NEWS International 17 (6).
- Rüttinger, D.; Zugmaier, G.; Nagorsen, D.; Reinhardt, C.; Baeuerle, P. A. (2008). "BiTE-Antikörper: Durch Bispezifität T-Lymphozyten gegen Tumorzellen richten" [BiTE antibodies: Directing T lymphocytes against tumor cells by bispecifity]. Journal Onkologie (in German) (4).
- "BiTE Antibody Platform". Micromet Inc.
- Nagorsen, D.; Bargou, R.; Rüttinger, D.; Kufer, P.; Baeuerle, P. A.; Zugmaier, G. (2009). "Immunotherapy of lymphoma and leukemia with T-cell engaging BiTE antibody blinatumomab". Leukemia & Lymphoma 50 (6): 886–891. doi:10.1080/10428190902943077. PMID 19455460.
- Clinical trial number NCT00635596 for "Phase I Study of MT110 in Colorectal Cancer (CRC), Gastrointestinal (GI) and Lung Cancer (MT110-101)" at ClinicalTrials.gov
- Amann, M.; d'Argouges, S.; Lorenczewski, G.; Brischwein, K.; Kischel, R.; Lutterbuese, R.; Mangold, S.; Rau, D.; Volkland, J.; Pflanz, S.; Raum, T.; Münz, M.; Kufer, P.; Schlereth, B.; Baeuerle, P. A.; Friedrich, M. (2009). "Antitumor Activity of an EpCAM/CD3-bispecific BiTE Antibody During Long-term Treatment of Mice in the Absence of T-cell Anergy and Sustained Cytokine Release". Journal of Immunotherapy 32 (5): 452–464. doi:10.1097/CJI.0b013e3181a1c097. PMID 19609237.
- Kischel, R et al. (2008). "Characterization in primates of MCSP- and CD33-specific human BiTE antibodies for treatment of Melanoma and AML". Proc Am Assoc Cancer Res 99. Abs 2404.
- Lutterbuese, R et al. (2008). "Conversion of cetuximab, panitumumab, trastuzumab and omalizumab into T-cell-engaging BiTE antibodies creates novel drug candidates of high potency". Proc Am Assoc Cancer Res 99. Abs 2402.
- Baeuerle, PA; Reinhardt, C (2009). "Bispecific T-cell engaging antibodies for cancer therapy.". Cancer Research 69 (12): 4941–4. doi:10.1158/0008-5472.CAN-09-0547. PMID 19509221.
- Kufer, P; Lutterbüse, R; Baeuerle, PA (2004). "A revival of bispecific antibodies.". Trends in Biotechnology 22 (5): 238–44. doi:10.1016/j.tibtech.2004.03.006. PMID 15109810.