期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 294, 期 16, 页码 6294-6305出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.006742
关键词
cancer therapy; T cell; antibody engineering; protein chimera; protein engineering; protein splicing; cancer immunotherapy; split protein; superantigen; T cell activation
资金
- Slovenian Research Agency [P4-0176]
Several antibody-targeting cancer immunotherapies have been developed based on T cell activation at the target cells. One of the most potent activators of T cells are bacterial superantigens, which bind to major histocompatibility complex class II on antigen-presenting cells and activate T cells through T cell receptor. Strong T cell activation is also one of the main weaknesses of this strategy as it may lead to systemic T cell activation. To overcome the limitation of conventional antibody-superantigen fusion proteins, we have split a superantigen into two fragments, individually inactive, until both fragments came into close proximity and reassembled into a biologically active form capable of activating T cell response. A screening method based on fusion between SEA and coiled-coil heterodimers was developed that enabled detection of functional split SEA designs. The split SEA design that demonstrated efficacy in fusion with coiled-coil dimer forming polypeptides was fused to a single chain antibody specific for tumor antigen CD20. This design selectively activated T cells by split SEA-scFv fusion binding to target cells.
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