期刊
PROTEIN ENGINEERING DESIGN & SELECTION
卷 30, 期 10, 页码 713-721出版社
OXFORD UNIV PRESS
DOI: 10.1093/protein/gzx051
关键词
Antibody; B7H6; cancer; chimeric antigen receptor; immunotherapy; single chain fragment variable
资金
- National Institutes of Health [R01 CA164178, F30 AI122970]
- National Institutes of Health Center of Biomedical Research Excellence [8P30GM103415]
- Elmer R. Pfefferkorn and Allan U. Munck Education and Research Fund at Dartmouth
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.
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