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Can I read The IgG4 hinge with CD28 transmembrane domain improves V~H~H-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer on EtoBox?
The IgG4 hinge with CD28 transmembrane domain improves V~H~H-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer by Nan Li; Alex Quan; Dan Li; Jiajia Pan; Hua Ren; Gerard Hoeltzel; Natalia de Val; Dana Ashworth; Weiming Ni; Jing Zhou; Sean Mackay; Stephen M. Hewitt; Raul Cachau; Mitchell Ho is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.
What is The IgG4 hinge with CD28 transmembrane domain improves V~H~H-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer about?
Heterogeneous antigen expression is a key barrier influencing the activity of chimeric antigen receptor (CAR) T cells in solid tumors. Here, we develop CAR T cells targeting glypican-1 (GPC1), an oncofetal antigen expressed in pancreatic cancer. We report the generation of dromedary camel V~H~H nanobody (D4)-based CAR T cells targeting GPC1 and the optimization of the hinge (H) and transmembrane domain (TM) to improve activity. We find that a structurally rigid IgG4H and CD28TM domain brings the two D4 fragments in proximity, driving CAR dimerization and leading to enhanced T-cell signaling and tumor regression in pancreatic cancer models with low antigen density in female mice. Furthermore, single-cell-based proteomic and transcriptomic analysis of D4-IgG4H-CD28TM CAR T cells reveals specific genes (e.g., __HMGB1__) associated with high T-cell polyfunctionality. This study demonstrates the potential of V~H~H-based CAR T for pancreatic cancer therapy and provides an engineering strategy for developing potent CAR T cells targeting membrane-distal epitopes.
Who reads The IgG4 hinge with CD28 transmembrane domain improves V~H~H-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer?
It is typically read by researchers, students, and practitioners in Biochemistry, Genetics and Molecular Biology.
- Author
- Nan Li; Alex Quan; Dan Li; Jiajia Pan; Hua Ren; Gerard Hoeltzel; Natalia de Val; Dana Ashworth; Weiming Ni; Jing Zhou; Sean Mackay; Stephen M. Hewitt; Raul Cachau; Mitchell Ho
- Publisher
- Springer Science and Business Media LLC
- Published
- 2023
- Language
- EN
- Field
- Biochemistry, Genetics and Molecular Biology (Life Sciences)