Targeting solid tumors via T cell receptor complementarity-determining region 3delta in an engineered antibody.
Human Vdelta2 gammadelta T lymphocytes killed multiple solid tumors, even displaying comparable therapeutic efficacy with anti-tumor chemical-cis-platinum in an adoptive experiment in both nude and SCID murine model shown in present study. We previously found that T cell receptor (TCR) gammadelta recognize tumors via complementarity-determining region 3 (CDR3), briefly named as CDR3delta. Based on characteristics of specific binding of CDR3delta to tumor targets, we developed a novel tumor-targeting antibody, whose CDR3 in heavy chain is replaced by CDR3delta sequence derived from human ovarian carcinoma (OEC) infiltrating gammadelta T cells (gammadeltaTILs). This CDR3delta-grafted antibody OT3 exhibited specific binding activities to OEC line SKOV3 both in vitro and in vivo, which included specific binding to several tumor cell lines, interacting with heat shock protein (HSP) 60 and triggering ADCC against tumors in vitro, as well as displaying tumor imaging by radioisotope 99mTc-labeled antibody OT3 in vivo. Moreover, immunotoxin OT3-DT, CDR3delta-grafted antibody OT3 chemically conjugated with diphtheria toxin (DT) showed the anti-tumor effect on the growth of several solid tumors including OEC, cervix adenocarcinoma, hepatocellular carcinoma, and rectum adenocarcinoma to various extents in nude mice. Therefore, we have found and confirmed a novel therapeutic strategy for targeting solid tumors, making use of immune recognition characteristics of gammadelta T cells.
Wang
Zhun
Z
Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China.
Zhang
Tie
T
Hu
Hongbo
H
Zhang
Huiyuan
H
Yang
Zhi
Z
Cui
Lianxian
L
He
Wei
W
D000818:Animals; D045744:Cell Line, Tumor; D022801:Complementarity Determining Regions; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D015202:Protein Engineering; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000737:chemistry* / Q000276:immunology; D020349:Surface Plasmon Resonance
D022801:Complementarity Determining Regions; D016692:Receptors, Antigen, T-Cell, gamma-delta