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词条 Bi-specific T-cell engager
释义

  1. Mechanism of action

  2. Examples

     Clinical trials  Further research 

  3. References

  4. Further reading

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 (fully owned subsidiary of Amgen Inc).[1]

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.[2][2]

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.[2][3]

This action mimics physiological processes observed during T cell attacks against tumor cells.[3]

Examples

Clinical trials

The following BiTEs are in clinical trials {{as of|2010|7|lc=on}}:

  • Blinatumomab (MT103): for the treatment of non-Hodgkin’s lymphoma and acute lymphoblastic leukemia; directed towards CD19, a surface molecule expressed on B cells[4]
  • Solitomab (MT110): for the treatment of gastrointestinal and lung cancers; directed towards the EpCAM antigen[5][6][7]

Further research

Utilizing the same technology, melanoma (with MCSP specific BiTEs) and acute myeloid leukemia (with CD33 specific BiTEs) can be targeted.[8] 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.[9] BiTEs against CD66e and EphA2 are being developed as well.[10]

References

1. ^{{cite web|title=US Trademark registration no. 3,068,856, serial number 78/040,636.|url=http://tarr.uspto.gov/servlet/tarr?regser=serial&entry=78040636|publisher=US Patent and Trademark Office}}
2. ^{{cite journal|journal=Journal Onkologie|title=BiTE-Antikörper: Durch Bispezifität T-Lymphozyten gegen Tumorzellen richten|trans-title=BiTE antibodies: Directing T lymphocytes against tumor cells by bispecifity|year=2008|issue=4|first1=D.|last1=Rüttinger|first2=G.|last2=Zugmaier|first3=D.|last3=Nagorsen|first4=C.|last4=Reinhardt|first5=P. A.|last5=Baeuerle|language=German|url=http://www.journalonko.de/aktuellview.php?id=1656}}
3. ^1 {{cite web|url=http://www.micromet.de/index.php?id=67|title=BiTE Antibody Platform|publisher=Micromet Inc}}
4. ^{{Cite journal | doi = 10.1080/10428190902943077 | title = Immunotherapy of lymphoma and leukemia with T-cell engaging BiTE antibody blinatumomab | pmid = 19455460 | year = 2009 | last1 = Nagorsen | first1 = D. | last2 = Bargou | first2 = R. | last3 = Rüttinger | first3 = D. | last4 = Kufer | first4 = P. | last5 = Baeuerle | first5 = P. A. | last6 = Zugmaier | first6 = G. | journal = Leukemia & Lymphoma | volume = 50 | issue = 6 | pages = 886–891 }}
5. ^1 2 {{cite journal|journal=Oncology NEWS International|volume=17|issue=6|date=1 June 2008|first=Caroline|last=Helwick|url=http://www.cancernetwork.com/display/article/10165/1165525|title=Novel BiTE antibody mediates contact between T cells and cancer cells}}
6. ^{{ClinicalTrialsGov|NCT00635596|Phase I Study of MT110 in Colorectal Cancer (CRC), Gastrointestinal (GI) and Lung Cancer (MT110-101)}}
7. ^{{Cite journal | first8 = D. | last9 = Volkland | last8 = Rau | first7 = S. | last7 = Mangold | first9 = J. | journal = Journal of Immunotherapy| pmid = 19609237 | issue = 5| pages = 452–464 | volume = 32 | last10 = Pflanz | first6 = R. | last6 = Lutterbuese | first1 = M. | first10 = S. | last2 = d'Argouges | last1 = Amann | last11 = Raum | year = 2009 | first11 = T. | last12 = Münz | first12 = M. | last13 = Kufer | first13 = P. | last14 = Schlereth | first14 = B. | last15 = Baeuerle | first15 = P. A. | last16 = Friedrich | first16 = M. | title = 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 | first2 = S. | last3 = Lorenczewski | last5 = Kischel | first5 = R. | first4 = K. | last4 = Brischwein | first3 = G. | doi = 10.1097/CJI.0b013e3181a1c097 }}
8. ^{{cite journal|title=Characterization in primates of MCSP- and CD33-specific human BiTE antibodies for treatment of Melanoma and AML|last=Kischel|first=R|journal=Proc Am Assoc Cancer Res|volume=99|at=Abs 2404|year=2008|url=http://www.micromet.de/fileadmin/template/main/pdf/download/AACR_2008_MCSP_CD33_BiTE_Poster.pdf|display-authors=etal|deadurl=yes|archiveurl=https://web.archive.org/web/20110719061528/http://www.micromet.de/fileadmin/template/main/pdf/download/AACR_2008_MCSP_CD33_BiTE_Poster.pdf|archivedate=2011-07-19|df=}}
9. ^{{cite journal|title=Conversion of cetuximab, panitumumab, trastuzumab and omalizumab into T-cell-engaging BiTE antibodies creates novel drug candidates of high potency|last=Lutterbuese|first=R|journal=Proc Am Assoc Cancer Res|volume=99|at=Abs 2402|year=2008|url=http://www.micromet.de/fileadmin/template/main/pdf/download/AACR_2008_Herceptin_BiTE_Poster.pdf|display-authors=etal|deadurl=yes|archiveurl=https://web.archive.org/web/20110719061543/http://www.micromet.de/fileadmin/template/main/pdf/download/AACR_2008_Herceptin_BiTE_Poster.pdf|archivedate=2011-07-19|df=}}
10. ^{{cite journal|last1=Baeuerle|first1=PA|last2=Reinhardt|first2=C|title=Bispecific T-cell engaging antibodies for cancer therapy.|journal=Cancer Research|volume=69|issue=12|pages=4941–4|year=2009|pmid=19509221|doi=10.1158/0008-5472.CAN-09-0547}}

Further reading

  • {{cite journal|pmid=15109810|year=2004|last1=Kufer|first1=P|last2=Lutterbüse|first2=R|last3=Baeuerle|first3=PA|title=A revival of bispecific antibodies.|volume=22|issue=5|pages=238–44|doi=10.1016/j.tibtech.2004.03.006|journal=Trends in Biotechnology}}
{{Engineered antibodies}}{{DEFAULTSORT:Bi-Specific T-Cell Engager}}

2 : Monoclonal antibodies|Immunology
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