Strictly Target Cell-dependent Activation of T Cells by Bispecific Single-chain Antibody Constructs of the BiTE Class
- 1 November 2007
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of Immunotherapy
- Vol. 30 (8), 798-807
- https://doi.org/10.1097/cji.0b013e318156750c
Abstract
Bispecific antibodies have been extensively studied in vitro and in vivo for their use in redirected tumor cell lysis. A particular challenge of bispecific antibody constructs that recognize the invariant CD3 signaling complex is a controlled polyclonal activation of T cells that, ideally, is exquisitely dependent on the presence of target cells. Otherwise, overt production of inflammatory cytokines and secondary reactions may occur as side effects, as can be observed with constitutively T-cell activating monoclonal antibodies to CD3 or CD28, and with bispecific antibodies bearing Fcγ portions. Here we analyzed 2 distinct bispecific single-chain antibody constructs of the BiTE class, called MT110 and MT103 (or MEDI-538), for conditional T-cell activation. In the presence of target-expressing cell lines, low picomolar concentrations of the BiTE molecules were sufficient to stimulate a high percentage of peripheral human T cells to express cytokines and surface activation markers, enter into cell cycle, and induce redirected lysis of target cells. However, in the absence of target cells, the 2 BiTE molecules even at high concentrations did not detectably activate T cells. Our data show that T cell activation by monomeric forms of MT110 and MT103 is highly conditional in that it is strictly dependent on the presence of cells expressing the proper target antigen. BiTE molecules therefore qualify for a highly controlled polyclonal T-cell therapy of cancer.Keywords
This publication has 28 references indexed in Scilit:
- Indoleamine 2,3-dioxygenase, tumor-induced tolerance and counter-regulationCurrent Opinion in Immunology, 2006
- TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillanceCancer Cell, 2005
- BiTEs: bispecific antibody constructs with unique anti-tumor activityDrug Discovery Today, 2005
- A revival of bispecific antibodiesTrends in Biotechnology, 2004
- High frequency of HLA-B44 allelic losses in human solid tumorsHuman Immunology, 2003
- Down-Regulation of HLA Class I Antigen-Processing Molecules in Malignant MelanomaThe American Journal of Pathology, 1999
- beta2-Microglobulin mutations, HLA class I antigen loss, and tumor progression in melanoma.JCI Insight, 1998
- Bispecific Monoclonal Antibody Therapy of B-Cell MalignancyLeukemia & Lymphoma, 1995
- Targeting of Anti-Tumor Responses with Bispecific AntibodiesImmunobiology, 1992
- Hybrid antibodies can target sites for attack by T cellsNature, 1985