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Protein Eng Des Sel. 2017 Oct 1;30(10):713-721. doi: 10.1093/protein/gzx051.

Development of unique cytotoxic chimeric antigen receptors based on human scFv targeting B7H6.

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Thayer School of Engineering, Dartmouth College, 14 Engineering Dr, Hanover, NH 03755, USA.
Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, 1 Medical Center Dr, Lebanon, NH 03756, USA.
Center for Synthetic Immunity, Geisel School of Medicine, Dartmouth College, 1 Medical Center Dr, Lebanon, NH 03756, USA.


As a stress-inducible natural killer (NK) cell ligand, B7H6 plays a role in innate tumor immunosurveillance and is a fairly tumor selective marker expressed on a variety of solid and hematologic cancer cells. Here, we describe the isolation and characterization of a new family of single chain fragment variable (scFv) molecules targeting the human B7H6 ligand. Through directed evolution of a yeast surface displayed non-immune human-derived scFv library, eight candidates comprising a single family of clones differing by up to four amino acid mutations and exhibiting nM avidities for soluble B7H6-Ig were isolated. A representative clone re-formatted as an scFv-CH1-Fc molecule demonstrated specific binding to both B7H6-Ig and native membrane-bound B7H6 on tumor cell lines with a binding avidity comparable to the previously characterized B7H6-targeting antibody, TZ47. Furthermore, these clones recognized an epitope distinct from that of TZ47 and the natural NK cell ligand NKp30, and demonstrated specific activity against B7H6-expressing tumor cells when expressed as a chimeric antigen receptor (CAR) in T cells.


Antibody; B7H6; cancer; chimeric antigen receptor; immunotherapy; single chain fragment variable

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